0:00

Welcome to the Found My Fitness

0:02

podcast. I'm your host Rhonda Patrick. Today's

0:04

episode features Dr. Peter Atiyah. Dr.

0:07

Peter Atiyah is a highly respected expert

0:09

in preventative medicine with a special focus

0:11

on applied science of longevity. His

0:13

deep engagement with the topic of longevity

0:16

is the cornerstone of his New York

0:18

Times bestselling book Outlive, the science and

0:20

art of longevity. Dr. Atiyah

0:22

also extends his expertise into his

0:24

clinical practice early medical and shares

0:26

his knowledge through his popular podcast.

0:28

Many of you are already aware

0:30

of the drive. In this episode,

0:32

you will learn why ApoB is

0:34

a superior predictor of cardiovascular disease

0:36

over LDL particle number and

0:38

managing the four main factors

0:40

that elevate ApoB. Why

0:43

ApoB exists in humans when it doesn't

0:45

in most species, whether or

0:47

not low LDL is a risk

0:50

factor for cancer and a variety

0:52

of other surprising facts about LDL

0:54

biology you really can't find anywhere

0:57

else. Peter's opinion on ApoB reference

0:59

ranges, whether there is an

1:01

ApoB level low enough that it

1:03

is impossible to die from atherosclerosis.

1:07

Which dietary factors increase ApoB?

1:09

How statins and other lipid

1:11

lowering pharmacotherapies work, including their

1:14

side effects and costs, and

1:17

what the alternatives are, the pros

1:19

and cons of different statin alternatives.

1:22

How increased muscle mass helps achieve

1:24

lower blood sugar levels, which may

1:27

play a pivotal role in reducing

1:29

overall mortality, and the

1:31

potential for glycemic control to

1:33

be suboptimal well before doctors

1:35

identify it. Peter's 80% zone 2

1:37

20% VO2 max training protocol. The

1:42

dangers of visceral fat and why

1:44

it correlates with increased cancer risk.

1:47

Peter outlines the benefits and risks

1:49

of aggressive cancer screening and offers

1:51

insights on optimal screening timing. He

1:53

also clears up misconceptions about the

1:56

radiation used in mammograms. The

1:58

hormonal changes of menopause and

2:01

their significant impact on women's

2:03

health, along with how hormone

2:05

replacement therapy influences the risk

2:07

of dementia, cancer, and heart

2:09

disease in women. Vitamin

2:11

D, sunlight versus supplementing and

2:13

optimal levels. Why symptoms

2:15

of low testosterone are often

2:17

more important than actual levels

2:20

when deciding whether or not

2:22

to go on testosterone replacement

2:24

therapy. Why Peter's recommended

2:26

testosterone replacement therapy dosing schedule

2:28

differs from the standard. Peter's

2:31

protocol for treating low testosterone

2:33

and why testosterone replacement therapy

2:35

isn't always the right answer. Methods

2:38

for lowering blood pressure, exercise,

2:40

nitrates, hot tub, and coco

2:42

flavanols. Peter's exercise, sleep,

2:45

nutrition, and alcohol routines for

2:47

optimizing longevity, and so much

2:49

more. Before we dive into

2:51

our discussion with Dr. Peter Ortea, I'd

2:53

like to highlight a valuable resource available

2:55

for you. It's a

2:58

comprehensive report I've compiled focusing

3:00

on evidence-based strategies to optimize

3:02

cognition and slow down brain

3:04

aging. This report

3:06

delves deep into the best

3:08

exercise practices for boosting brain-derived

3:10

neurotrophic factor, a key

3:12

neurotrophic factor integral to learning,

3:15

memory, mood regulation, and

3:17

combating brain aging. Additionally,

3:20

it encompasses a range of

3:22

lifestyle approaches, including specific protocols

3:24

for heat exposure through sauna

3:27

or hot baths, along with

3:29

detailed guidance on omega-3 and

3:32

polyphenol intake, all targeted

3:34

at elevating brain-derived neurotrophic factor

3:36

levels. You can

3:39

find that detailed protocols

3:41

report at bdnfprotocols.com. Once

3:46

again, that's

3:48

bdnfprotocols.com. And

3:51

now, on to the podcast with Dr. Peter

3:53

Ortea. Hi, everyone. I'm

3:55

sitting here with the amazing Dr.

3:58

Peter Ortea. you

4:00

don't need an intro to him. He

4:03

has changed our

4:05

understanding of the scientific

4:08

literature, preventative medicine with

4:11

respect to longevity, improving

4:13

health span. He's a number

4:15

one New York Times bestselling

4:17

author of the book Outlive,

4:19

amazing book. Also he

4:21

has a very popular podcast on

4:23

health and medicine, one of

4:26

the few podcasts that I listened to called

4:28

The Drive. And he's also a

4:32

renowned speaker, so public speaking he does a

4:34

lot of that as well and you can find a lot

4:36

of lectures he's given on YouTube. So

4:38

I'm very excited to be sitting here with you

4:40

today Peter and having this conversation you

4:42

were on the podcast many years ago,

4:44

about eight years ago. Yeah I was gonna say 2016 right?

4:47

I think it may

4:49

be earlier. You might have been like 2015. You might

4:51

have been one of the like the first I

4:54

don't know six or seven guests I mean you were

4:56

like one of the first guests that I had on

4:58

the podcast. It was a long time ago. You were

5:01

still at New Sea. Yeah. So

5:03

it was a while ago. Well thank you for

5:05

having me back. So let's dive

5:07

into like maybe a general

5:10

question that I kind of have for you which is

5:12

what ignited

5:14

your interest in the

5:16

field of longevity? I

5:18

mean I think it's a it was kind

5:20

of an intersection of two things but but I think

5:23

the the critical spark was the birth of my daughter

5:26

and I write about this a little bit in the book

5:28

but you know I think you know

5:30

I'm in my mid 30s she's born and

5:32

all of a sudden that became

5:35

a manner in which

5:37

I contemplated my own mortality and

5:41

I it's not like I hadn't been

5:43

aware or had been blind to my family history

5:45

but I have a very bad family history for

5:47

cardiovascular disease and so now the

5:49

idea that I had this daughter and boy

5:52

she was like I mean

5:54

I I just adored her more than I

5:56

could have imagined during my wife's

5:58

pregnancy. It was so real

6:01

and I also kind

6:03

of realized, if

6:06

I don't figure out what's going on here,

6:08

I'm going to potentially leave

6:10

this planet sooner than I would like and therefore

6:13

leave her and potentially other kids

6:15

to come along. So it

6:17

was really those two things that really

6:19

catapulted me into, at the time, just

6:22

trying to understand everything I could with

6:24

respect to cardiovascular disease. That became my

6:26

initial obsession. So it was really less

6:28

about longevity and more about

6:30

that, but of course, once you dive into that,

6:32

you realize, well, what

6:35

does it benefit you if you figure out how to not

6:37

die of heart disease, but you die of some other thing?

6:40

Or what does it, eventually, what does

6:42

it benefit you to delay your death but

6:45

have a lousy quality of life? So then, all

6:47

of these things just came as an evolution out of that. It's

6:50

funny because I actually have a very similar

6:52

story about the birth of my

6:54

son and my, I

6:56

mean, I remember times

6:58

like, within the first couple

7:00

of years of my son being born, going for my long runs

7:03

and stopping in the middle of my run

7:05

and literally bawling my eyes out because I

7:09

knew there was a time that I was going to be gone and he was

7:11

going to be without me. And it was

7:13

so hard to think about that. And

7:17

so, everything that you

7:19

just said completely resonates with me, where

7:22

it's like, I want to be around when

7:24

my grandkids are getting older.

7:27

I want to be not only around, but I want to be jumping

7:29

rope with them. I want to teach them to jump rope. And

7:32

so, all of those things have sort of crossed my

7:34

mind at the same time. With

7:37

respect to the cardiovascular disease

7:40

that you mentioned and you talk about this in the

7:42

book as well, there's a

7:45

statistic that I've read from

7:47

the National Health Statistics

7:49

website, which is that every

7:52

33 seconds, someone

7:55

dies from cardiovascular disease in the United

7:57

States. When

8:00

people hear the word cardiovascular disease, at

8:02

least even me, the cardiovascular disease, what

8:04

is that, what does it mean? Where

8:06

is atherosclerosis coming into play? Where does

8:08

coronary heart disease, what is

8:10

cardiovascular disease? I mean,

8:13

you could define it very broadly and

8:15

include valvular disease and cardiomyopathies and all

8:17

of those things, but when we talk

8:19

about ASCBD, atherosclerotic

8:22

cardiovascular disease, which is the leading cause of

8:24

death in the United States and globally, it's

8:26

the leading cause of death for men and

8:28

women. What

8:30

we're referring to is the disease of

8:33

coronary arteries that leads to ischemia. And

8:36

just to take a step back for a moment, when

8:38

you think about all of these chronic diseases, which I'm

8:40

sure we'll get into today, cancer, neurodegenerative diseases, et cetera,

8:43

things that you and I have spoken about a lot, including when

8:45

you were on my podcast, it's

8:48

important to understand that this is the disease for which

8:50

we have the clearest understanding. So

8:53

our understanding of

8:55

what initiates and propagates cancer

8:57

is very small compared to

8:59

our understanding on the cardiovascular front. Our understanding

9:02

of this on the neurodegenerative side is also

9:04

quite small. There are still many things we

9:06

don't understand. So, you

9:08

know, everything we're about to talk about on the

9:10

cardiovascular side should be at least thought

9:12

of in the context of how wonderful is

9:14

it that we understand these things because we

9:17

have the most tools for prevention here. So

9:19

with that said, what

9:21

we're really talking about that does the lion's share

9:23

of killing, and again, I'll bracket for a moment

9:25

that there are other things. There are people that

9:28

are dying from, you know, cardiomyopathies, there are people

9:30

that are dying from valvular cardiovascular disease and things

9:32

of that nature. But

9:34

the majority of what's happening is

9:36

a disease that leads to plaque

9:39

formation inside of coronary arteries, and we can

9:41

go as deeper, as shallow as you want

9:43

into that and why that happens and how

9:45

that's a function of endothelial injury, lipoprotein

9:48

burden, and inflammation. But

9:51

this leads to a reduction

9:53

in blood flow to key

9:56

parts of the heart muscle. And when that

9:59

happens, the heart... undergoes an ischemic event.

10:01

Now, sometimes that can be chronic and

10:03

sometimes that can be acute. And if

10:05

an acute event occurs in

10:07

a region where enough muscle of the heart is

10:09

compromised, that's going to result in sudden death, that's

10:11

a heart attack. And it's important

10:13

to understand that a

10:17

little up, when I was in medical school, it was more than

10:19

50%. It's now a little less than

10:21

50% but it's still a very high number.

10:24

A little less than 50% of people's

10:26

first brush with a symptom of coronary

10:28

artery disease is sudden death. That's

10:31

worth repeating because we couldn't, I still remember being

10:33

asked this question in medical school. You're sitting there

10:35

as a first year medical student

10:37

in cardiovascular pathology class and the

10:39

pathologist said, what's the single most

10:41

common presenting feature for someone

10:44

having cardiovascular disease the first time?

10:46

And everyone was like chest pain, shortness of breath,

10:48

rattling off all these real stuff. He goes, no,

10:50

sudden death. Again

10:53

today, it's not quite 50% but

10:56

that's a very sobering statistic. Absolutely.

10:59

I do want to

11:01

dive into some of the major

11:03

causes of the atherosclerosis

11:05

and the atherosclerotic cardiovascular disease that

11:08

you're talking about. So lipoproteins,

11:11

you mentioned and

11:14

most people know, they

11:16

hear about lipoproteins, they hear about LDL

11:18

or HDL but ApoB,

11:23

why should people know about ApoB? Well,

11:26

again, I think it's worth maybe just

11:29

getting everybody on the same page with cholesterol.

11:31

Let's start with that. So everybody's heard of

11:33

cholesterol and I think most people would probably

11:36

even have a negative valence when they think about

11:38

it's like cholesterol is a bad thing. So

11:42

it's worth explaining that that's not really true. Cholesterol

11:44

is an essential thing. So without

11:47

cholesterol, we wouldn't be alive and there

11:50

are really rare fortunately genetic conditions

11:52

in which cholesterol synthesis is compromised

11:55

and those tend to be fatal

11:57

in utero. can't

12:00

make enough cholesterol, it ceases to

12:02

exist because cholesterol is the thing

12:05

that gives every cell fluidity, the membrane of every

12:07

cell fluidity and it's the precursor to some

12:09

of the most important hormones we make. So in the

12:11

case of us as humans, right, testosterone,

12:14

estrogen, progesterone, cortisol, these essential

12:16

hormones are all made from

12:18

cholesterol. So every cell in

12:20

the body with the exception of red blood

12:22

cells makes plenty of cholesterol. The

12:25

lion's share of it is probably done by the liver and

12:27

the steroidal tissues and

12:30

we have to figure out a way to move this

12:32

stuff around the body and the highway system of the

12:34

body is the blood and the blood of

12:36

course is water. So if

12:39

we want to move things that are water

12:41

soluble throughout the body like proteins and ions,

12:43

it's easy because they dissolve freely in water

12:45

and they move around. But when

12:47

you want to move something around water that

12:49

is not water soluble such

12:51

as cholesterol as a lipid, you

12:53

have to wrap it in something that is

12:56

water soluble and that something

12:58

is the lipoprotein. And

13:00

the big protein on the

13:02

surface of that sphere is

13:04

called an apolipoprotein. And

13:07

there are broadly speaking two classes

13:09

of apolipoproteins. There are the A

13:11

class and the B class. So

13:15

some of the lipoproteins are wrapped

13:18

in an apolipoprotein called apob100 and

13:20

we just abbreviate that to apob

13:23

but I'll just say it this one time and

13:25

we'll never talk about it again. There's also an

13:27

apob48 that wraps another type of

13:29

lipoprotein called achylomicron. We won't talk about

13:32

that again because it doesn't really factor

13:34

into cardiovascular disease. So apob

13:36

is short for apolipoprotein

13:39

B100 which is

13:41

the structural apoprotein that

13:43

sits on low

13:46

density lipoproteins abbreviated

13:48

LDLs. Intermediate

13:50

density lipoproteins abbreviated IDLs, very

13:53

low density lipoproteins abbreviated VLDLs.

13:56

The ApoAs and this is big A

13:58

never to be confused. with ApoA which

14:01

we may talk about, those

14:03

wrap the family of high

14:06

density lipoproteins. They're much more

14:08

complicated than ApoBs believe it or not

14:10

and there are many of them but

14:12

nevertheless, broadly speaking, that's

14:14

what's going on. So why

14:16

do we care about all this stuff? Well, in

14:19

the 1950s when it became

14:22

clear that cholesterol was playing a

14:24

role in cardiovascular disease, the

14:28

first observation was people with very, very,

14:30

very high total cholesterol because at the

14:32

time, that was all that could be

14:34

measured was total cholesterol. By

14:37

the way, what that meant was the total

14:39

amount of cholesterol in all of your

14:41

lipoproteins, in your HDLs, in

14:43

your LDLs, and in your

14:45

VLDLs. Those three lipoproteins constitute

14:48

the amount of total cholesterol you

14:50

have in the lipoproteins. We

14:52

can come back to this idea because it's important. That

14:54

represents about 10% of the total cholesterol in your body.

14:58

The total cholesterol concentration

15:01

was loosely correlated with cardiovascular

15:03

outcomes but only at

15:05

extremes, meaning if you took people whose

15:07

total cholesterol was in the top 5% and

15:10

compared them to people whose total cholesterol was in the bottom 5%,

15:13

there was a clear association with cardiovascular

15:15

disease. March forward

15:17

many, many decades, we came to

15:19

realize that actually this low density lipoprotein

15:21

which is a subset of your total

15:24

cholesterol, if the cholesterol contained within the

15:26

low density lipoproteins, that's much more strongly

15:28

associated. And

15:30

what we now know is the case

15:32

is there's an even better way to

15:34

predict risk than just saying how much

15:36

cholesterol is contained within the low density

15:38

lipoproteins. A better way to predict risk

15:40

is to add up the concentration of

15:43

all the ApoB particles. So

15:46

that number ApoB measured in

15:48

milligrams per deciliter is

15:50

the concentration of the entire

15:52

burden of particles that are capable of

15:55

undergoing something that I'm sure we'll talk

15:57

about which is the initiation and progression

15:59

of atherosclerosis. So how how

16:01

the apo be number Can

16:04

you talk about how that so you

16:06

mentioned LDL total total LDL cholesterol? That

16:10

number is like some of it's like determined

16:12

by some equation, right? And we can be

16:14

but it can also be measured directly. Yeah,

16:16

so there's what that be particle number of

16:18

his car yeah, and so there's there's two

16:20

ways to go about doing this so in the Olden

16:23

days and unfortunately many labs still do this.

16:25

They rely on an equation called the Friederwald

16:27

equation So total cholesterol

16:30

is relatively easy to measure you

16:33

so you draw the plasma you spin it down

16:35

and You basically lice

16:37

all of the lipoproteins and you can

16:39

measure total cholesterol So if you if

16:41

you just basically apply something to lice

16:43

all of the proteins You'll

16:46

you'll say all the lipoproteins you'll say total

16:48

cholesterol is 200 milligrams per deciliter Then

16:51

they directly also measure two other things.

16:53

They can directly measure total triglyceride Concentration

16:57

and using a separate assay they

16:59

can measure the total concentration of

17:01

cholesterol within the HDL particles So

17:04

now you've measured total

17:07

cholesterol HDL cholesterol

17:09

and triglyceride the Friederwald equation stems

17:11

from an observation that kind of

17:13

sort of on average sometimes VLDL

17:17

cholesterol is approximately

17:19

1 5th the triglyceride

17:22

concentration So the Friederwald

17:24

equation is quite literally used to

17:26

estimate LDL as follows LDL cholesterol

17:28

is estimated as total cholesterol Less

17:31

HDL cholesterol less triglyceride concentration

17:33

divided by 5 if

17:36

you're doing everything in milligrams per deciliter and Unfortunately,

17:39

most labs still do that So

17:41

when you look at your cholesterol

17:44

report, it'll say LDL see it'll

17:46

give a number and unless it

17:48

says Direct you can assume they've

17:51

done the Friederwald equation, which is I've

17:53

seen that wrong more often than I'm seeing it, right? A

17:56

good lab will do a direct assay. They

17:58

will actually measure LDL cholesterol concentration and they

18:00

will give you in milligrams

18:02

per deciliter the total concentration of LDL-C. That

18:06

is still an inferior predictor of

18:08

risk relative to APO-B. Yes.

18:11

Okay. So let's, the reason I

18:13

wanted to mention that LDL-C is because as you

18:15

mentioned, many labs do measure it indirectly

18:18

and there are many

18:20

types of LDL, right? So there are

18:22

different densities and sizes. I'm curious about

18:25

what your thoughts are on the

18:28

different sizes of like more atherogenic sizes

18:30

of LDL such as the smaller dense

18:32

particles and you

18:35

know, like how you view

18:37

that, like the different particle sizes

18:40

and the particle number and then of course

18:42

APO-B. So like the whole... I

18:45

mean, there's been a big evolution in the

18:47

way we've practiced medicine in our practice with

18:49

respect to this. So 10 years ago,

18:51

we were looking at LDL

18:54

particle number which the

18:58

both the Mesa population, so the

19:00

multi-ethnic study of atherosclerosis and the

19:02

Framingham offspring population

19:04

have both demonstrated unequivocally that

19:07

when you compared LDL particle

19:09

number to LDL cholesterol, LDL

19:12

particle number always predicted risk

19:14

better than LDL cholesterol. So how would

19:16

you do this? You

19:18

would follow people longitudinally for

19:21

cardiovascular events and you would

19:23

do this in sort of a like

19:25

a cumulative insulin incidence graph. So on

19:28

the x-axis, you have time on the

19:30

y-axis, you have incidence of cardiovascular disease

19:32

and you plot out everybody as a

19:34

function of whether LDL-C

19:38

was higher or lower than as

19:40

a percentile than LDL-P. So LDL-P

19:42

stands for the number of particles,

19:44

LDL-C is the concentration

19:47

of cholesterol. And

19:49

this was again unequivocally the case. Particle

19:51

number always predicted better. So

19:53

how do you count the number of particles? Well, it turns

19:55

out there are different ways to do this. You can do

19:58

this using NMR. clear

20:00

magnetic resonance is like how an MRI works. So

20:02

it's applying a magnetic field. It's basically doing, I

20:04

mean, this is being a little cheeky, but it's

20:06

sort of like doing an MRI on the blood

20:08

and you can count the number of particles that

20:11

way. That's not actually the gold standard, but that's

20:13

the way it's most commonly done in clinical practice.

20:15

It can also be done with ion motility. We

20:18

switched from NMR to ion motility

20:20

for LDL-P because it was more

20:22

accurate. But ultimately, I mean,

20:25

this is now about five years ago, we

20:27

actually switched to ApoB, which was superior on

20:29

all fronts. And here's the reason why. First

20:32

of all, there are different ways in labs

20:34

to do this. So LabCorp, for example, and

20:36

Boston Heart have different magnets and different algorithms

20:38

for how they run their LDL-P. So if

20:40

you run an LDL-P on each of those

20:42

labs, you'll get a different number. That's

20:45

a bit disturbing to me. I want to know

20:47

that the ApoB that I get at one lab

20:49

is the same as the ApoB I get at

20:51

another lab and it's standardized across all fronts. But

20:54

there's a more important reason why I favor

20:56

ApoB over LDL-P and that is it

20:59

encompasses the total atherogenic burden.

21:02

And you can get burned and

21:04

fooled by patients who have very

21:06

high VLDL, meaning they

21:08

have a high burden of very low density lipoproteins,

21:11

even if their LDL burden is low. So

21:14

I won't go into it because it's so

21:16

nerdy. It's not worth getting this deep in

21:19

the weeds. But there are certain genetic conditions

21:21

where people have completely normal LDL, that

21:24

very elevated VLDL and

21:26

they have a very high atherogenic risk. And

21:28

you will miss that if you're looking at LDL-P

21:30

or LDL-C. You will not miss that if you're

21:33

looking at ApoB. What

21:36

about the fact that it's small

21:39

dense LDL, which has been shown to

21:41

be more atherogenic? So ApoB does become,

21:44

so you mentioned that the structural role of

21:46

ApoB in the lipoproteins is very important. It

21:48

also plays a role, as you mentioned, in

21:50

allowing the lipids to

21:53

be soluble in the

21:55

plasma. But it plays a role also in research.

22:00

cycling so it gets you know, it interacts with the

22:02

LDL receptor and can be taken back up in the

22:04

liver. The small dense LDL

22:06

particles, ApoB is somewhat obscured as the

22:08

LDL particle gets smaller in size and

22:10

more dense. Therefore, it's not

22:12

too... Harder to clear. Harder to clear, exactly. So

22:15

what about in the case and the reason I'm asking

22:18

is because as you mentioned, ApoB

22:20

is on VLDL, IDL, LDL, right?

22:23

But there's different sizes of the LDL

22:26

and the larger more

22:28

buoyant LDL is better

22:30

than having a higher proportion of the smaller

22:33

dense LDL. Right, but that's why

22:35

ApoB captures that risk, right? So in

22:38

other words, this is another reason why

22:40

I think that ApoB is the great

22:42

equalizer because once you have

22:44

the ApoB concentration, you're

22:46

accounting for the fact that clearance is going down.

22:48

I mean, the one way

22:50

to think about this is anytime

22:52

you see an elevated ApoB, it always

22:55

comes back to something on the clearance

22:57

side is not working. Now there are

22:59

really broadly speaking when I talk about

23:01

this with patients, I go through the

23:03

four sort of pillars

23:05

of what elevates ApoB. So

23:07

it can be driven by cholesterol synthesis

23:10

and we can talk about that because it's going to factor into you

23:13

know, dietary choices for example. So certain

23:15

dietary patterns will lead to higher LDL

23:17

than others. It's

23:19

impacted by cholesterol reabsorption.

23:22

So we can talk about what the

23:24

life cycle of cholesterol is but again, it's you

23:26

know, we make it and we reabsorb it and

23:28

it gets circulated. It can have

23:30

to do with triglyceride burden. So this

23:33

is where insulin resistance really factors

23:35

in to how ApoB can

23:37

go up and ultimately

23:39

it comes down to clearance and

23:41

clearance has everything to do with the

23:43

presentation of the LDL receptor on the liver,

23:46

the confirmation of it, the number of

23:48

them and how long they survive on

23:50

the liver. And all of these things

23:52

have an enormous effect, some of which

23:54

we can manipulate with drugs. So for

23:57

example, all drugs that are

23:59

used to treat LDL in

24:01

some way or another indirectly or

24:03

directly impact the LDL receptor. Some

24:05

do it really directly like a

24:07

PCSK9 inhibitor directly does that by

24:09

targeting a protein that breaks down

24:11

LDL receptors. So anyway,

24:15

a long-winded way of saying this is

24:17

another advantage of APOB is

24:19

it allows you to in one

24:22

measurement capture all of that risk because

24:25

if you have small if you have

24:28

you know two individuals like if you're just

24:30

using LDL-P as your risk

24:32

you might miss some of the elevated

24:34

BLDLs. If you're looking at LDL-C you'll

24:37

clearly miss some of the size issues

24:40

that should be captured in LDL-P. But

24:43

again, I guess maybe what

24:45

you're asking is if you have a

24:47

low APOB but they're all small is

24:49

that worse than having a low APOB

24:51

where they're all big and the answer

24:53

is probably

24:56

but you'll also see that in the like

25:00

there are other metrics that are kind of coming

25:02

on board now which are looking at LDL triglyceride

25:04

levels. So you can look at the degree to

25:06

which the LDLs are cholesterol depleted and

25:08

that can also give you a sense of risk.

25:10

The question is is that a first or second order

25:12

term and I think the first order term is still

25:14

going to be the number of particles. That's the

25:16

biggest driver of risk and everything

25:19

else factors into it. In other words, that's not

25:21

an independent risk because it's driven by the residence

25:23

time of the LDL which is driven by the

25:25

clearance rate. So let's talk

25:27

about like the number so

25:29

the LDL I sorry the APOB number

25:31

because like if most people

25:33

go to a standard lab and they measure their APOB

25:36

there's a reference range and it says you know

25:38

okay if you're less than 80 milligrams

25:41

per deciliter. You're excellent. Okay.

25:44

Yeah. Where does that

25:46

number come from and you know

25:49

what like

25:51

it has anyone measured APOB levels

25:53

across the lifespan. Do

25:56

we know like is there a correlation

25:58

with APOB levels and the beginning findings

26:00

of atherosclerosis, if someone done those

26:02

studies, you know, that sort of

26:05

thing. Yeah. So the reference ranges

26:07

are purely population-based distribution questions. So

26:09

every lab will have a different

26:11

way of doing this but a

26:14

general, you

26:16

know, sort of philosophy for labs is, you

26:19

know, let, you know, so for the lab we

26:22

use and by the way, we completely ignore these

26:24

reference ranges there but they're there, we can't avoid

26:26

them, they're there and we explain to our patients

26:28

that we're going to editorialize on top of them.

26:30

But, you know, the reference lab we use will

26:32

say APO below 80 is wonderful. Well, 80 just

26:34

happens to be the 20th percentile of the population.

26:37

It will say 80 to 100 is intermediate or 80

26:39

to 120 it says is intermediate

26:41

risk and above 120 is very high

26:43

risk. So in for the lab we

26:45

use, we know that 80 is the 20th

26:48

percentile, 120 is

26:50

the 80th percentile or the 60th percentile, I can't

26:53

remember. So it's literally just

26:55

putting you up against a population distribution

26:57

and that's it. Now,

26:59

our philosophy on APO B is

27:01

completely different and as

27:04

you may recall, I devote actually quite a bit

27:06

of real estate to this in the book because

27:08

I think it is such an important concept and

27:11

it is, in my opinion,

27:13

certainly top three failures of

27:16

medicine 2.0 is

27:18

in failing to appreciate the point I'm about

27:20

to make which

27:23

is that once you understand the

27:25

causality of APO B, meaning

27:28

once you understand that APO B is

27:30

not just associated with cardiovascular disease but

27:33

it's causally linked to it

27:35

meaning it causes ASCVD. To

27:39

get into this discussion about managing

27:41

10-year risk, thinking about being in

27:43

this percent versus this percent makes

27:46

no sense. When you have causal

27:48

things that cause disease, you eliminate them and

27:51

the analogy I use is cigarettes with lung

27:53

cancer. So nobody

27:56

disputes that cigarettes are causally

27:58

linked to lung cancer. cancer. They

28:01

are. It's as clear as Tuesday

28:03

follows Monday. But

28:05

people forget that causality doesn't

28:07

mean everybody who smokes will get lung cancer

28:09

and it doesn't mean that every person with

28:11

lung cancer smoked. So

28:14

you don't need to be necessary and

28:17

sufficient, necessary or sufficient to still be

28:19

causal. But our

28:21

approach to patients who

28:23

smoke is very clear which

28:26

is never smoke and

28:28

if you do smoke, stop immediately. Do

28:31

we look at people who smoke and say well, once

28:34

your 10-year risk of lung cancer reaches this

28:37

threshold, we're going to tell you to stop

28:39

smoking. Or once your pack

28:41

year smoking is above the

28:43

50th percentile or the 80th percentile, we're

28:46

going to tell you to stop. Absolutely

28:48

not. You immediately eliminate

28:50

smoking. And so similarly,

28:53

it makes no sense that we would

28:55

look at a causal driver of ASCBD

28:57

in the case of ApoB and

29:00

kind of take an approach of well,

29:02

being at the 20th percentile or the 30th percentile

29:05

or the 40th percentile is acceptable. None of those

29:07

things really make sense. You have something that is

29:09

causing the disease, you should eliminate

29:11

it as soon as possible because it is

29:13

an area under the curve problem. So

29:16

atherosclerosis begins at

29:18

birth. When you

29:20

do autopsies on people who are very

29:22

young, in fact, in the book include

29:24

a photo of a guy

29:26

who, you know, a man I forget, I think

29:28

maybe 26 years old who was a victim of

29:30

a homicide or something. So a completely unrelated death.

29:34

But you look at the autopsy sections

29:36

of his coronary arteries. I mean, he

29:39

already had very advanced atherosclerosis. Now, it

29:41

wasn't clinically relevant. It wasn't going to

29:43

kill him anytime soon. But

29:45

the point is this is

29:47

a disease that takes decades to progress.

29:51

And one of the biggest drivers of

29:53

it in addition to things like high

29:55

blood pressure and smoking and insulin resistance

29:57

is ApoB. So to be

29:59

able to take But

32:01

before that time, the LDL

32:04

did serve that purpose too. And

32:06

that's why he thinks, you know, it's kind of

32:08

a relic left over where the reason why we're

32:10

constantly making it is because it's a very large

32:12

protein in size. It's like tens

32:15

of millions of like the

32:17

unit versus like 50,000 or something. It's very big.

32:19

And so it takes time to make it. And

32:23

so I was, you know, I was thinking,

32:25

well, like inflammation also does make it go

32:27

up even further at the level of synthesis.

32:30

I don't know exactly the clearance, you

32:32

know, how it's regulating clearance. But do

32:35

you think the aging process is mostly affecting

32:37

the clearance of it or? My

32:40

intuition is yes. My intuition is that

32:42

it's primarily impacted on the clearance level,

32:45

which is going to be against some

32:47

facet of LDL-R, LDL-R beating LDL receptor.

32:49

So is it we are making less

32:51

of them? They are

32:53

surviving less. The

32:56

proteins that, you know, and that can

32:58

basically done there are many ways to

33:00

regulate that process. But that's my intuition

33:02

is it's less a conformational change in

33:04

the LDL-R and more a number of

33:06

them and or a reduced amount

33:08

of time that they stay present. One thing I'll add

33:10

on the evolutionary front, you know, I had a guy

33:13

named John Castellan on my podcast a

33:15

few months ago and he proposed

33:17

a really interesting idea which completely

33:19

makes sense evolutionarily, which you could

33:21

argue sort of like we

33:23

don't really need Apo B. Like

33:26

this is the other thing, like most species

33:28

don't have Apo B. They

33:31

don't require LDL. But

33:34

how I mean... They have cholesterol but they

33:36

don't require... Transporting all

33:38

these, you know. You can do it with HDL. You

33:41

can transport everything with HDL. Yeah.

33:44

Okay. They don't need the

33:46

LDL. HDL was always going in reverse, like

33:48

it was bringing everything back to... No,

33:51

it's actually much more complicated. I mean, in

33:53

us LDL is doing the majority of what's

33:55

called reverse cholesterol transport. So RCT, which is

33:57

kind of like the good movement of cholesterol.

34:00

you sort of think of the bad movement

34:02

as taking cholesterol into the arteries, the good

34:04

movement is taking it back to the liver

34:06

and us LDL is doing the majority of

34:08

that. So, HDLs are typically transferring their cholesterol

34:11

to LDLs and LDLs are bringing them back to

34:13

the liver. But

34:15

John made an interesting point, right? Which

34:17

is that, you know, in

34:20

sort of following up on what you said,

34:22

the evolutionary cost of making

34:24

cholesterol is enormous. I mean,

34:27

it's a very labor intensive step, right? I

34:29

can't remember the number of ATP's that are

34:32

required to make a molecule of cholesterol, but

34:34

it's in the tens, right? Like it

34:36

could be 40 or something to that effect. And

34:39

so, we evolved

34:41

to have a system that prioritized

34:44

having a lot of cholesterol, being

34:47

able to keep a lot of it around. Because

34:50

again, this was an energy conserving system. Now,

34:52

this serves as no benefit today. Because today,

34:54

we can make plenty of it and we

34:56

are we are in an energy abundant environment,

34:58

which we were not in that, you

35:01

know, hundreds of thousands of years ago. And

35:04

so, this is a bit of an

35:06

unfortunate vestige of our past, it much in the

35:08

way that a lot of the things

35:11

that lead to insulin resistance are a vestige

35:13

to things that were once very valuable. I

35:15

mean, the things that allowed us to leap

35:17

up out of the swan with our swamp

35:20

with big brains was our primarily our capacity

35:22

to store excess energy in a way that

35:24

even primates can't get

35:26

served us really well until 150 years

35:28

ago. And I think the same is probably

35:30

true of a cholesterol and ApoB. So,

35:32

going back to your question, how

35:35

much ApoB is enough? Well, it turns out you don't

35:37

really need any of it to be perfectly fine. So,

35:40

if you look at a child, they're born

35:42

with an LDL cholesterol or ApoB level, typically

35:45

below 20 milligrams per deciliter. So,

35:48

a kid, if you think about it, has

35:51

the greatest need for growth,

35:54

right? Like, so you think about the

35:56

cholesterol demand of myelinating the entire central

35:58

nervous system, all of You

38:00

know, I imagine like everybody walks around and

38:02

you've got a graph that on the x-axis

38:04

is time and on the y-axis is apo

38:06

B and you have a curve and you

38:08

want to figure out what the area under

38:11

that curve is. And

38:13

we want to minimize the area under that curve.

38:15

So if you took... Exactly.

38:17

So if you took... So again, very similar to

38:19

smoking, right? We talk about risk

38:21

in pack years of smoking. So

38:24

if a person smokes a pack a day

38:26

for 20 years or two packs a day

38:29

for, you know, 10 years,

38:31

you know, you have a way of kind of comparing

38:33

apples to apples on those things. So

38:36

to have a lifetime ceiling of

38:38

60 would also be a very,

38:41

very low risk individual. 60

38:43

milligrams per deciliter is about the

38:45

fifth percentile at the adult population

38:47

level. So then that comes

38:50

back to my question... Sorry, one of the things

38:52

I read out... That's the lifespan. When like... Yeah.

38:56

When do you start measuring this? Like people aren't measuring

38:58

their apo B in their, you know, teenage is one...

39:00

Yeah, I mean, I would argue we should be. But

39:02

I want to go back and say one other thing

39:04

about your question, which I should

39:06

have mentioned earlier, which is it also

39:08

depends on other risk factors. So there

39:10

are really four big things that are

39:13

driving risk causally. Apo

39:15

B is one, insulin

39:17

resistance is one, hypertension

39:20

is one and smoking is one.

39:22

Apo Bs are the big four. So

39:25

you have to take everything we're saying

39:27

on the apo B front and acknowledge

39:30

that those other things are also causally

39:32

linked to ASCBD. So

39:34

again, it's a difficult situation

39:36

to imagine, but it's certainly at least

39:38

theoretically plausible. You have somebody whose apo B

39:40

is at 60, but they have uncontrolled

39:43

hypertension, type two diabetes and they

39:45

smoke. I

39:47

mean, you could certainly arrive at that situation pharmacologically,

39:49

you're probably not going to arrive at that situation

39:51

naturally. Would I

39:53

say that that person is free and clear? No, I wouldn't.

39:56

So we, you know, at the outset,

39:58

I mentioned how the... the

40:01

downside of talking about ASCBD is it's the

40:03

number one killer. I mean, it's, you

40:05

know, in fact, when you talk about it

40:07

globally, the gap between ASCBD and cancer is

40:10

even bigger. It's like 19 million people annually

40:12

to 12 or 13 million for cancer. I

40:14

mean, it's an enormous difference. But

40:17

the good news is our understanding

40:19

mechanistically of what drives this is

40:21

so clear and our tools for

40:23

prevention are some

40:25

of the best and most benign. So

40:29

let's say that a person

40:32

is relatively

40:34

healthy, you know, they're committed to exercise or

40:36

they're not insulin resistant. I do want to

40:39

talk about hypertension, insulin resistance. But okay,

40:41

healthy, generalized, quote unquote, healthy person,

40:43

right? Once to

40:45

lower their APO B, they

40:47

want to try everything through diet, through lifestyle.

40:50

And you mentioned there are some major lifestyle

40:53

dietary factors that can increase APO B.

40:56

So let's talk about those. What are the so

40:58

the big two are anything that contributes to

41:00

insulin resistance. So we'll start with that. And

41:02

that does so mostly

41:05

through the VLDL triglyceride pathway. So we

41:07

talked earlier about it how there are

41:09

really two ways we make LDL, we

41:11

make LDL directly, we but most of

41:13

the LDL is made through VLDL. So

41:15

if you're exporting a lot of VLDL,

41:18

what you're doing is both making a lot of

41:20

that lipoprotein, but you also have a lot of

41:23

triglyceride in it. Now something I didn't mention a

41:25

moment ago that's worth restating or stating in the

41:27

first place. The LDL

41:29

is carrying around both

41:32

cholesterol and triglyceride. And

41:35

the more cholesterol there is, all things

41:37

equal, the more LDL you need. But the

41:40

same is true with triglyceride. So

41:44

the first mechanism in which we

41:46

see a very clear relationship between

41:48

diet and APO B is

41:50

the higher the burden of triglycerides, the

41:53

higher the burden of APO B. To

41:56

state this another way, if you take

41:58

two people who have the exact same

42:00

level of LDL cholesterol and

42:03

the same total cholesterol but one

42:05

has very high triglycerides and one has

42:07

very low triglycerides, the

42:10

former is going to have a much higher APOB and

42:13

therefore be at a much higher

42:15

risk of atherosclerosis because they have more

42:17

cargo and therefore require more ships in

42:19

the analogy of cargo being cholesterol

42:21

and triglycerides and the ships being the

42:24

lipoproteins. So step

42:26

number one is lower the triglyceride

42:28

as much as possible and

42:31

the triglyceride being low is an

42:34

enormous proxy for insulin sensitivity. So

42:36

this is one of the important

42:38

ways in which managing insulin resistance

42:41

is a key to keeping APOB in check and

42:44

of course there are other issues as well. So

42:46

insulin and glucose by themselves when

42:49

elevated also create problems at

42:51

the endothelial level which becomes another mechanism

42:53

by which this is problematic. It's

42:58

pretty clearly observed from a

43:00

dietary pattern perspective that carbohydrate

43:02

restriction is the most effective

43:05

tool at triglyceride reduction. All

43:07

carbohydrates, I mean like vegetables, furs, no,

43:10

no, no, no, no, yeah, refined and

43:12

starchy carbohydrates, yeah. So but

43:15

that actually feeds really nicely into

43:17

the next observation which is what's

43:19

the next dietary pattern that impacts

43:22

APOB and that saturated fat consumption?

43:25

And the reasons for that

43:27

are twofold. So the first is that

43:30

saturated fat directly impacts cholesterol

43:32

synthesis. Now this is

43:34

not true equally of all saturated fats but we

43:36

don't really have great data on if

43:39

certain saturated fats have a greater

43:41

impact on cholesterol synthesis relative

43:43

to others. For example, a C16

43:45

might be potentially more so than

43:48

a C18 or a C19. But again... What

43:50

foods would you find a C16? Oh, like a

43:52

C16 would be more in I believe like a

43:55

coconut oil or a palm oil or something like

43:57

that. Very good. Also,

43:59

by the way, that would be... also see that more a C16

44:01

like a palmitate would be more of a saturated

44:03

fat you see in response

44:06

to insulin resistance. So it would actually be a

44:09

de novo saturated fat

44:11

synthesis. So perhaps,

44:14

so I think that's a big part of it. I think

44:16

cholesterol synthesis is a big part of it. I think a

44:18

bigger part of it might be that

44:20

excess saturated fat inhibits

44:23

the sterile binding, the sterile regulatory

44:26

binding protein in the liver that

44:29

results in fewer LDL receptors

44:32

being made. So

44:35

saturated fat therefore has two things that

44:37

it's doing that are driving up ApoB

44:40

and the susceptibility of this

44:42

varies from different individuals. So

44:45

I was on a ketogenic diet for three years. I

44:48

was not one of the people who seemed to suffer

44:50

from this. So even on a ketogenic diet where I

44:53

was getting 80% of my calories from

44:55

fat and probably half of that was saturated fat,

44:58

I did not have any sort

45:00

of obnoxious increase in my

45:02

ApoB or LDLC or any of these metrics.

45:05

Similarly, we have some patients who were on very

45:08

low carb, very high fat diets. Some

45:10

of them have completely normal levels of

45:12

lipids and some of them have lipids

45:14

that go absolutely haywire. So it's not

45:16

entirely clear what the difference

45:18

is but clearly there are different

45:20

genes that will allow certain people

45:22

to metabolize that saturated fat safely

45:25

while others do not. So I'm

45:27

not in the camp that believes

45:29

that and there is an

45:31

entire camp of people who believe this that if

45:33

you're on a low carb, high fat diet and

45:35

your ApoB and LDLC go through the roof, it's

45:37

not problematic. I don't believe that at all. I

45:39

think that that's a very bold claim and I

45:41

would not be willing to play that game. I

45:44

think if your ApoB goes haywire, even

45:46

if you're very insulin sensitive and even

45:48

if you're in energy balance and all the other

45:50

wonderful things that might come with your ketogenic diet,

45:52

I think you have to pay Very

45:56

close attention to if your lipids get

45:58

out of whack. Those.

46:00

Are basically your big manipulations?

46:03

Dietary wise, it's. The. Composition

46:05

Of Fact The quantity and composition. A Fat.

46:07

And. The dietary choices that

46:09

that address insulin sensitivity. So in

46:12

the people that let's say that they're eating

46:14

a higher saturated fat diet. And

46:16

is they swap? That. Out with monounsaturated

46:18

Saturday than polyunsaturated fat, which some

46:20

can fall. Selected Denies the kind

46:22

of polyunsaturated road, but it's a

46:24

swap that out. There

46:27

a puppy levels in our in

46:29

our experience about Sas of the

46:31

people. Who have. This.

46:33

Hyper response to saturated

46:36

fat. If you iso

46:38

caloric li. Shift. Them

46:40

to high mana one saturated fat. You fix the

46:42

problem. Yeah, okay, it starts

46:44

to get into a little bit of an

46:46

issue right? Which is and it misses where.

46:49

You. Know you have to remember what problem

46:51

you're solving. So. For

46:53

some people, that's an easy switch. You know,

46:55

because they were kind of. Some people tend to go out of their

46:58

way to try to eat as much saturated fat as boss one. Not

47:00

sure why. like they sort of. The. Other like okay,

47:02

well I'm doing this, you know, kitaj and diet and. I'm.

47:04

Just gonna basically eat coconut oil and

47:07

palm oil like it's my job. Yeah,

47:09

and and so to the zebra. You

47:11

just gotta say do like, stop doing

47:13

that like. Use. Olive oil on

47:16

your salad and like let's be reasonable and

47:18

then it fixes everything on the for other

47:20

people you know it's it's a just can't

47:22

be addressed and. And. I've

47:24

heard other people say oh, you know this crazy

47:26

like we know that. You. Know: excessive

47:28

sat restriction in the diet will lower

47:30

cholesterol and that's true. I mean if

47:32

you. Go. On a

47:34

really draconian sat lowering

47:36

diet, you will lower

47:38

your cholesterol. Might

47:41

view clinically is that makes very

47:44

little sense. Because.

47:48

That. Using some to the whole bunch of

47:50

other issues. So a lotta times when I

47:52

see people on these excessively restrictive satin lowering

47:54

die it's. actually become

47:56

insulin resistant lot of them because they're

47:58

really over to the consuming a lot of

48:00

poor quality carbs and

48:03

they're suffering other consequences of

48:05

really low fat intake. Now again, this doesn't mean

48:07

that a low fat diet is necessarily problematic. The

48:09

devil's in the details here, just like, you know,

48:11

the devil's in the details on what

48:14

constitutes a reasonable versus an unreasonable

48:16

low carb diet. But the point

48:18

I try to make to people is I believe

48:21

that using nutrition to solve the

48:23

lipid problem is not a good

48:25

solution. I think use nutrition

48:28

to solve the nutrition problem. Use

48:30

nutrition to address energy balance, protein

48:33

needs, anabolic structure, energy, all of these

48:35

other things and let your lipids fall

48:37

where they may because this is one

48:39

of the few areas in medicine where

48:41

we have amazing pharmacologic tools. Most of

48:43

medicine doesn't really have great pharmacology if

48:45

you stop to think about it. Like,

48:48

we don't have great, there's nothing pharmacologically

48:50

that's adding brilliance to our Alzheimer's

48:52

prevention strategy or our

48:54

cancer prevention strategy. I mean, we

48:57

have some stuff but it's nothing compared to what we

48:59

can do with blood pressure and lipid management. So, I

49:02

always say it's hard enough to find the right diet that's

49:04

going to work for you in terms of

49:06

your ability to be compliant with it, your ability to

49:08

be within energy balance which is the single most important

49:10

thing, your ability to be insulin sensitive, your ability to

49:12

get adequate amounts of protein. If

49:15

you solve that with a low fat diet that also

49:17

happens to keep your lipids low, great. But

49:19

if you solve that with a higher fat diet that

49:22

does everything perfect for you except your lipids go

49:24

haywire, don't put your head in the sand

49:26

and act like having lipids that have gone haywire is

49:28

a good thing. No, just acknowledge it's not a good

49:30

thing but we can fix it with, again, myriad tools

49:32

that didn't exist 20 years ago. Are

49:35

there people that are genetically,

49:37

have genetically

49:39

low ApoB and if so, what's

49:41

their cardiovascular

49:43

mortality, they all cause mortality?

49:47

Yeah, so there are people, so it turns

49:49

out ApoB and LDLC are highly genetic which

49:51

is what has allowed us to do the

49:53

Mendelian randomization studies that act as one of

49:56

the, there are basically three cornerstones

49:58

of data that make unambiguously

50:00

clear of the relationship between LDL

50:03

or APO-B and ASCVD. So you

50:05

have all of the epidemiologic data,

50:07

which again epidemiology is rife with

50:09

problems, but you know when

50:12

the data is pretty much all in the same

50:14

direction and you have the dose

50:16

effect and all these other things it becomes

50:18

quite helpful. You have all the clinical trial

50:20

data which I would divide into primary and

50:22

secondary prevention data and then you have the

50:24

Mendelian randomization data which again for listeners is

50:27

basically any time there is a

50:29

biologic variable of interest that is

50:31

under a high degree of genetic

50:33

control and produces a high degree of variability

50:35

in the population, you

50:37

can look at how nature has

50:40

basically randomized it across people and

50:42

you can look at outcomes of

50:45

interest. So in the case of

50:47

LDLC, because we know it is

50:49

highly genetic, right, this is clear

50:51

in that, and I don't just

50:53

mean in extreme cases but just

50:55

across a population, you can see

50:57

that lower lifelong exposure to APO-B

51:00

or LDL produces lower ASCVD risk

51:02

over a lifetime. So using

51:06

this we can say there

51:08

are people at really low and high extremes. So

51:10

at the high extreme you have the people who

51:13

have what's called familial hypercholesterolemia, which is a genetically

51:17

heterogeneous disease, meaning

51:19

there are literally thousands

51:21

of mutations that result in a similar

51:24

phenotype. The phenotype is defined as having

51:26

an LDL cholesterol off-medication of more than

51:28

190 milligrams per deciliter and there's a

51:30

couple of other criteria but just to

51:33

give you a sense of how high

51:35

the LDL needs to be to meet

51:37

that criteria. At

51:40

the other end of the spectrum we have these people

51:42

with very, very low LDL-C or APO-B

51:45

and the most interesting group of

51:47

these are the people who are

51:49

folks that have a hypo-functioning gene

51:52

for PCSK9. So Helen

51:54

Hobbs made this

51:56

discovery in probably

51:59

the early The Two Thousands My vague recollection.

52:01

I remember reading this paper When it came

52:03

out, it was a really mind boggling paper.

52:06

Call it like summer. Two thousand, forty thousand,

52:08

Five thousand six Somewhere that neighborhoods which is

52:10

harrys their These people walking around with. Ldl

52:13

see have like ten to twenty milligrams per

52:16

deciliter. And. And these

52:18

are adults by to You normally would never see that

52:20

in adults and they weren't doing anything different. I did,

52:22

just. Like they weren't on some

52:24

crazy diet or clearly weren't take any medication.

52:26

It's a nice people were found to have.

52:29

A mutation in their Pc as

52:32

canine gene that rendered a hyper

52:34

functioning protein and Ptsd nine is

52:36

a protein degrades Ld on recent

52:38

years snow. And. Subset of

52:40

these people they're mirror opposites were

52:42

discovered several years earlier which had

52:45

a hyper functioning Pc as canine

52:47

gene. Or I prefer a

52:49

gene that pretty cyber functioning protein.

52:51

And these people had sky high

52:53

Ldl cholesterol. They were a subset

52:56

of the familial hypercholesterolemia syndromes and

52:58

these people weren't. And what was

53:00

interesting to note is that they

53:02

cinderella cardiovascular disease. So.

53:05

I'm. At a kit

53:07

tell you what their life expectancy is

53:10

because I haven't I haven't looked at

53:12

those data but what I did confirm

53:14

as. They have no

53:16

increase in the incidence of any other disease.

53:19

So. In other words, They're. Absent A A

53:21

C B D but they don't make up for

53:23

it with more cancer and when original disease or

53:25

more diabetes. That's that's interesting.

53:28

For a couple of reasons. One ah,

53:30

you'd see on Twitter a lot You

53:32

know that the very, very. You

53:35

now since insists the hyper focused

53:37

very low carb community that like

53:39

you know that they. They share

53:41

studies about a low cholesterol. People with

53:43

low cholesterol have a higher all cause

53:46

mortality. They're more likely to die from

53:48

in all these different causes of death.

53:50

With yeah, the problem with those studies

53:52

is a minute. The. only

53:55

address this one's because it i've done so much

53:57

addressing this that i realize you you can only

53:59

way some time preaching to an audience that actually

54:01

has no interest in understanding the truth. But

54:04

just to give you an example of the type of

54:06

biases that creep into those studies, when

54:09

you look at people who have very

54:11

low LDL cholesterol, you're sampling a subset

54:13

of people who are at very high

54:16

risk for a disease, typically two diseases,

54:18

right? When you have very high LDL,

54:20

you are at risk of ASCVD, cerebral

54:23

vascular disease, and Alzheimer's disease, and all

54:25

causes of dementia. So therefore, the

54:27

people who are at high risk for those are typically the

54:29

people at a population level who have the

54:31

lowest level because they're being treated the most

54:33

aggressively. So this is

54:35

kind of the problem with that stuff. I'll

54:38

give you an example. There's a clear

54:40

association in the epidemiology. It doesn't come up

54:42

often, but it's come up from time to time

54:45

that the lower the LDL cholesterol, the higher the

54:47

risk of cancer. This

54:49

is a great example of when Mendelian

54:51

randomization becomes very valuable because you can

54:53

actually go back and look at the

54:56

genes that are controlling LDL. You

54:58

can look at how those are spread out, and you can ask

55:00

the question, once you just

55:02

look at the random assignment of those genes

55:04

that control LDL cholesterol, does that have any

55:07

bearing on cancer outcome? And the answer is

55:09

unequivocally no, it does not. So

55:12

when you do the MR, you get

55:14

the answer that the epi is clearly

55:16

confounding with something else, which is, in

55:19

other words, low LDL at the population

55:21

level is a proxy for other illness.

55:24

This is the issue here. Yes, thank you. The

55:27

other interesting point was with the actual gene

55:30

that you were mentioning, the PCSK9, right?

55:33

So when you were talking about

55:35

we have pharmacological interventions that do very

55:38

nicely lower APOB, one

55:43

of them is... PCSK9 inhibitors. Exactly.

55:45

Came right out of Helen Hobbs' observation. So

55:48

I want to... Let's

55:50

touch on the pharmacological treatments,

55:52

but also the

55:55

PCSK9 inhibitors. They're not necessarily

55:57

available to everyone at the start, right out

55:59

the gate. And then

56:01

I want to get your thoughts on some of

56:03

the base editing trials that

56:06

have started looking at literally like

56:08

you're doing a gene edit and

56:10

you're changing a nucleotide to essentially

56:14

make a PCC or the people

56:16

that you're talking about walking around

56:18

with no ASCV. Okay,

56:23

so let's maybe just talk broadly about what

56:25

the different pharmacologic strategies are, right? So the

56:27

very first drug that

56:29

was ever used to lower lipids was

56:33

a drug called, oh god,

56:36

I'm always blanking on the name of this, like tri-paranol.

56:41

So this was done in the 1950s. You never heard of

56:43

it. Yeah, well there's a reason you never heard of it, right? So it

56:45

turned out to be a really bad drug. So there used to be a

56:47

day when, again, in the 1950s and 1960s, we just didn't

56:50

know what the

56:52

hell was going on. So the idea was if you came

56:54

up with any drug that lowered cholesterol, it must be a

56:56

good thing. Well, it turned out

56:58

this drug lowered cholesterol by inhibiting an

57:01

enzyme that was

57:03

the final enzyme in this step that

57:05

we used to make cholesterol. So we

57:08

make cholesterol using two pathways, but one

57:10

of the pathways results

57:12

in a molecule called desmosterol, which

57:14

gets converted into cholesterol. So

57:17

there's an enzyme that facilitates that and

57:19

this drug blocked that enzyme. And as

57:21

a result, cholesterol levels went down. And

57:24

although no one was really paying attention at the

57:26

time, desmosterol levels went sky-high. And

57:30

it lowered cholesterol. So on the basis of that, this

57:32

drug was approved. And back at the time, that was

57:34

the only thing you were monitoring was total cholesterol. But

57:37

it was found that the patients on this drug, even

57:39

though they had lower cholesterol, had a higher incidence of

57:41

heart attacks. So the drug was ultimately pulled

57:43

in the 1960s. We now

57:46

know today that it was almost assuredly the case

57:48

that the desmosterol was even more

57:50

atherogenic than the cholesterol, or at

57:52

least as atherogenic. So

57:55

fast forward to the 1980s. The next

57:57

class of drugs is developed called...

58:00

bile acid sequesterance. We didn't really get into the life

58:02

cycle of cholesterol so it might be worth doing that

58:04

now because it'll make sense in the context of the

58:06

drug. So every cell in the body is

58:08

making cholesterol so just think

58:10

path one synthesis of cholesterol. If you

58:13

synthesize less cholesterol that's one way to

58:15

lower it. As you noted

58:17

all that cholesterol is making its way back to the liver.

58:20

When the liver gets a hold of all

58:22

that cholesterol it's putting a lot of it

58:24

into bile and we're using

58:26

bile acids to digest food. So as

58:28

bile via the bile duct is entering

58:31

the small intestine it is full of

58:33

cholesterol. The

58:35

body reabsorbs much of

58:37

that cholesterol. So each of the

58:39

enterocytes which are the gut cells

58:41

that line your intestine they

58:44

have a couple of transporters on them.

58:46

So one of the transporters on them it's called

58:49

a Neiman-Pixie one like one transporter. It

58:51

absorbs all of the sterols

58:54

and this is I use the word

58:56

sterile very carefully to distinguish it here

58:58

from just cholesterol. This is zoo sterile and

59:00

plant sterile which is or an animal

59:02

sterile which is called cholesterol. It absorbs

59:04

that all. There are

59:08

basically regulatory steps inside the cell that determine

59:10

how much of that should be kept and

59:12

how much should be excreted and a fraction

59:14

of that then gets excreted through an ATP

59:16

binding cassette. So point being

59:18

that's a second point of regulation at

59:20

the absorption site. But again this is

59:22

not the cholesterol we eat. This

59:25

is unesterified cholesterol. It's easy to get

59:27

in and out of the body. A

59:29

esterified cholesterol can't be absorbed and

59:31

most of the cholesterol we eat is esterified. That's why

59:33

we just poop it out. So

59:38

bile acid sequesterance which were the first version

59:40

of drugs the second version I guess of

59:42

drugs to lower cholesterol which are not used

59:44

today blocked that process in a

59:47

very crude mechanical way. They sequestered the

59:49

bile acids and dragged all the cholesterol

59:51

out the GI tract. They were not

59:53

a very successful class of drugs and

59:56

not the least of which because the side effects were

59:58

pretty bad. So it

1:00:00

really wasn't until the mid to late 80s, I

1:00:02

think 1987 if my memory serves me correctly, that

1:00:07

the first statin came to

1:00:09

be developed. And that was the

1:00:11

real turning point in basically

1:00:15

the pharmacologic

1:00:19

tool that became valuable against ASCVD. Now,

1:00:21

the first, second, and third generation statins

1:00:23

of that era are no longer in

1:00:25

use today because their side effect profile

1:00:27

was very harsh relative to what we

1:00:30

can do today. So

1:00:32

there are currently seven statins in

1:00:34

existence and each of them,

1:00:36

you know, offers some strengths and advantages over others.

1:00:38

And they're not a benign class of drugs. So

1:00:40

to be clear, they're an effective class of drug.

1:00:42

They're very effective at lowering LDL

1:00:45

cholesterol. They work by inhibiting

1:00:47

the first committed step of cholesterol synthesis.

1:00:51

They do that everywhere but primarily in

1:00:53

the liver. And the response

1:00:55

of the liver when cholesterol synthesis

1:00:57

is being shut down, the

1:00:59

liver says, I got to get more cholesterol in here. And

1:01:02

what does it do? It puts a whole bunch more

1:01:04

LDL receptors all over the liver. And

1:01:06

that's what's primarily driving down

1:01:08

LDL in the presence of a statin.

1:01:11

But the side effects are what? Well,

1:01:14

about 7% of people develop muscle aches on statins. So

1:01:16

if you think about how many people are on those

1:01:18

drugs or how many people are prescribed those drugs, that's

1:01:20

a huge number of people. The good

1:01:22

news is that's a completely reversible side effect. So

1:01:25

you put a person on a statin, they experience

1:01:27

muscle soreness, you take them off, it's gone within

1:01:29

a week or two. The

1:01:32

other big side effect, the one that

1:01:34

I probably think about the most is

1:01:36

insulin resistance. So a

1:01:39

very small subset of people, about 0.4% of

1:01:41

people put on a statin might go on

1:01:43

to develop type 2 diabetes as a result

1:01:45

of it. Now I think any

1:01:48

doctor who lets a patient get to the point where they

1:01:51

get type 2 diabetes because of their statin hasn't been paying

1:01:53

attention. We want to know

1:01:55

the minute you're becoming insulin resistant in response

1:01:57

to the statin. And those data are less

1:01:59

clear. exactly how

1:02:01

many people are getting insulin resistant, but

1:02:03

this isn't a reason to be paying

1:02:05

attention to bigger markers and more important

1:02:07

markers than just hemoglobin A1c trips

1:02:10

over the threshold of 6.5 percent. You have type

1:02:12

2 diabetes. Here you want to be able to

1:02:14

say, is the hemoglobin A1c moving?

1:02:16

What's happening to the fasting insulin and glucose in

1:02:18

these other markers? Does a patient wear a CGM?

1:02:20

One of the reasons we like CGM's on patients

1:02:22

when we put them on statins is we

1:02:25

have a historical level of what their glucose

1:02:27

control looks like and if all of a

1:02:30

sudden their baseline average glucose goes up

1:02:32

by 10 milligrams per deciliter which I've seen

1:02:34

in patients on a statin. I know.

1:02:36

That's not just a quick dietary trigger. Especially

1:02:38

when you take them off the statin and

1:02:40

it comes right back down to normal. So

1:02:42

even though they haven't gone to the level

1:02:45

of being diabetic, they're clearly becoming insulin resistant.

1:02:47

The third thing we see with statins is

1:02:49

an increase in the transaminases

1:02:51

or the liver function test. The liver

1:02:54

function test is a bit of a misnomer because

1:02:56

the transaminases really tell us more about inflammation than

1:02:58

function. So all

1:03:00

that said, statins are still kind of,

1:03:04

you know, they're doing the lion's share of the

1:03:06

work in this area but by no

1:03:08

means should we say that that's the only thing that we have

1:03:10

at our disposal. About 20 years ago

1:03:12

another drug called azetamide. Can I interrupt for a second

1:03:14

and ask you about statins? Yeah, of course. Okay. Because

1:03:16

I have some questions about them. So and

1:03:21

I'll never forget this conversation that again I had

1:03:23

with our mutual friend Ron Kraff because

1:03:25

he worked down the hall. I worked down the hall from him

1:03:27

and I collaborated with some of his postdocs and,

1:03:31

you know, they would come over and show me data

1:03:33

and we would talk because, you know, I had a

1:03:36

lot of experience in asking

1:03:38

mitochondrial function and mitochondrial

1:03:40

biology during graduate school.

1:03:43

And I remember saying this

1:03:46

to Ron, I'm like, you know, so

1:03:49

statins are affecting the HMG

1:03:51

CoA pathway that you mentioned, the cholesterol

1:03:53

synthesis, which also is important for the

1:03:56

synthesis of ubiquinol, right?

1:03:58

This is an important. coke

1:04:00

you can as I should probably call it. This

1:04:03

is important for mitochondrial function. I

1:04:05

mean, it's necessary for mitochondrial function

1:04:07

for transferring electrons across the

1:04:09

electron transport chain, which is essentially coupling

1:04:11

the oxygen we breathe with

1:04:13

the food that we eat to make energy.

1:04:16

And I remember saying, oh, so statins have

1:04:18

a side effect of targeting mitochondria. And he

1:04:20

said to me, no,

1:04:22

it's a direct effect. So

1:04:25

what are your thoughts

1:04:27

on how statins are

1:04:29

affecting mitochondria and

1:04:32

through this pathway? And obviously,

1:04:34

you might mention supplementation with a, you

1:04:37

know, measuring

1:04:41

mitochondrial function in terms of

1:04:44

BOTU max something. Yeah. So it's a

1:04:46

great question, actually, and something I have

1:04:48

thought a lot about. So

1:04:51

the literature has nothing to offer here, unfortunately.

1:04:54

So I wish I could say, you know,

1:04:56

Rhonda, the answer is this, because here's what

1:04:58

the literature says. Here's what

1:05:00

I can tell you. And

1:05:02

this is not going to be a satisfying answer. If

1:05:05

there is an impact on mitochondrial

1:05:07

function with statin use,

1:05:10

it's very small based

1:05:12

on what I consider to be

1:05:14

the single best measurement we have

1:05:16

to measure mitochondrial function, which is

1:05:18

zone two testing with lactate production.

1:05:22

So I know you know what this is because

1:05:24

we talk about this stuff all day long, but

1:05:26

just for folks listening, this

1:05:28

requires a little bit of explanation, but it's very important. And

1:05:30

I think it's I'm glad you brought this up.

1:05:32

So everybody understands what

1:05:35

the mitochondria do. If they're, you know, listeners of

1:05:37

your podcast, we don't need to explain the mitochondria.

1:05:40

But it's important to understand that

1:05:42

a functional test is a very important test

1:05:44

in medicine. We don't have many functional tests,

1:05:46

right? Most of the things we talk about

1:05:49

are biomarkers. And

1:05:51

by themselves, they don't tell you a huge amount

1:05:53

of information. They tend to be

1:05:55

quite static and not dynamic. But

1:05:58

we understand... that

1:06:00

the healthier an individual is,

1:06:03

the more they can rely on

1:06:05

their mitochondria for ATP generation under

1:06:07

increasing demands of the cell. This

1:06:10

is one of the hallmarks of health. And

1:06:13

by extension, one of the hallmarks of aging

1:06:15

and one of the hallmarks of disease is

1:06:18

an inability to do that. Meaning,

1:06:21

as the ATP demand on a

1:06:23

cell goes up, there is

1:06:25

an earlier and earlier shift to

1:06:28

glycolysis as opposed to

1:06:30

oxidative phosphorylation. So

1:06:33

how do we measure that clinically? Well,

1:06:35

we can put a person in, because

1:06:38

we can't, rather than test a cell, let's test

1:06:40

the whole organism, right? So we put a person

1:06:43

in sort of an ergometer, right?

1:06:45

So on a treadmill or on a bike

1:06:47

or under some sort of demand where we

1:06:49

can control the work that they

1:06:51

have to do. And we

1:06:53

can drive up the amount of work they

1:06:55

do while sampling lactate.

1:06:58

And why does that, what does that tell us? Well, just

1:07:00

to remind everybody, glucose

1:07:03

enters a cell and

1:07:05

it basically has two fates, right?

1:07:07

So glucose will be converted into

1:07:09

pyruvate regardless. It has

1:07:11

the fate at which oxygen is plentiful

1:07:13

and the body has the time to

1:07:15

make a lot of ATP where it

1:07:17

goes into the mitochondria. And

1:07:19

it has the less efficient

1:07:22

but quicker way to get ATP, which is

1:07:24

converting lactate, pardon me, pyruvate into lactate. So

1:07:27

this is the glycolytic

1:07:29

pathway versus the oxidative phosphorylitic

1:07:31

pathway. The

1:07:35

longer a cell can stay in

1:07:37

that mitochondrial space, the better

1:07:39

it is. It makes way more ATP and

1:07:43

it accumulates less lactate and hydrogen ion.

1:07:45

And the more lactate and hydrogen ion

1:07:47

you accumulate, eventually the cell becomes effectively

1:07:50

poisoned by that hydrogen ion and it

1:07:52

becomes very difficult for a muscular cell

1:07:54

to contract. So we

1:07:56

use this test with patients. This is

1:07:58

one of the. most important metrics we

1:08:01

care about. Literally, it would be in the

1:08:03

top 10 things we care about for our

1:08:05

patients, which is how many

1:08:07

watts can you produce on

1:08:09

a bike, or how many METs can

1:08:11

you exercise at on a treadmill or

1:08:13

whatever vehicle you're using while

1:08:15

keeping lactate below about two

1:08:17

millimole. Two millimole

1:08:19

is about the threshold beyond

1:08:21

which you are now

1:08:24

shifting away from the maximum capacity

1:08:26

of the mitochondria to

1:08:29

undergo this process. Okay,

1:08:31

all of this is to say, I

1:08:33

have clearly seen the effect of

1:08:36

a drug like metformin at impacting

1:08:38

that. Metformin,

1:08:40

which is a mitochondrial toxin,

1:08:42

right? Metformin impairs complex one

1:08:45

of the mitochondria. We

1:08:47

immediately see a change in

1:08:49

the lactate performance curve of

1:08:51

an individual on metformin. We

1:08:54

see a complete reduction in their zone

1:08:56

two output. They hit that

1:08:58

lactate of two much sooner. We

1:09:01

also see an increase, not big,

1:09:03

but significant, meaning clinically significant, in

1:09:06

their fasting, resting lactate level.

1:09:09

So all things equal, their lactate is just

1:09:11

getting higher. To

1:09:13

me, by the way, I don't know if

1:09:15

that's necessarily harmful. I don't think it's a

1:09:18

good idea, which is why I don't believe

1:09:20

in metformin as a giroprotective agent. I think

1:09:22

metformin is a good drug for someone who's

1:09:24

diabetic. If they can't exercise enough and they

1:09:26

can't get into energy balance. But

1:09:29

I don't think metformin is a great drug for

1:09:31

someone like you or someone like me. We

1:09:35

don't see this with statins. So

1:09:39

if it's happening, if- Does dependent

1:09:41

or- Just don't see it. Yeah,

1:09:43

just don't see it. So

1:09:45

it could be happening, but we don't have the

1:09:47

resolution to measure it. So that's why I'm

1:09:49

saying, I think one always has to

1:09:51

have the humility, which I hope I have, to say, look,

1:09:53

I don't know. But what

1:09:56

I do know is if there's an

1:09:58

effect there, it's really small. Now,

1:10:00

you mentioned ubiquinol or CoQ10 and there are

1:10:03

two states of it, ubiquinol and ubiquinone, but

1:10:05

ubiquinol would be the state we would want

1:10:07

to consider here. There have

1:10:09

been a number of clinical

1:10:11

trials looking at using or

1:10:13

supplementing ubiquinol with patients taking

1:10:16

statins. They have mostly done

1:10:18

this to assess the

1:10:21

muscle soreness issue. So they've mostly done this

1:10:23

as a way to ask the question, can

1:10:25

you reduce the incidence rather

1:10:28

of muscle soreness with statins? I

1:10:30

haven't looked at those literature in a couple of years.

1:10:32

The last I looked at them, there was still no

1:10:35

difference. That

1:10:37

said, we have patients that

1:10:39

really feel strongly about taking ubiquinol

1:10:42

when they're on a statin and I don't have any

1:10:44

issue with that. I don't think there's any

1:10:46

harm in taking it. I really don't think there is. And

1:10:50

if there's a chance of benefit, then I would say let's take

1:10:52

it. But again, unless

1:10:55

something has happened in the last couple of years that

1:10:57

I'm unaware of, I don't think

1:10:59

we have great data that ubiquinol offsets that.

1:11:02

And more importantly to your point, it's

1:11:04

not clear to me that that

1:11:06

effect translates to a functional deficit

1:11:08

in the mitochondria. When

1:11:11

you're measuring, so using

1:11:14

the zone to lactate threshold training to

1:11:16

kind of measure mitochondrial

1:11:18

function. So

1:11:23

buying the lactate meter,

1:11:25

nova by a medical or something

1:11:27

like that. Yeah, it's like a yellow-purple one. I

1:11:30

got it per your recommendation, but

1:11:32

for people listening if they want

1:11:34

to get one. But also knowing

1:11:37

how, you know, because there's, when you

1:11:39

go to like any sort of, if you were to

1:11:41

go talk to an exercise physiologist and you see lactate

1:11:43

threshold, like they kind of know. And

1:11:46

they're going to push you up. Lactate threshold is a different

1:11:48

number. Right. So this is like lower

1:11:50

level. This is below your lactate threshold.

1:11:52

Yeah, this is lower. So how

1:11:55

do people know, like let's say they have a

1:11:57

Peloton at home. Okay, and they get on their

1:11:59

Peloton. I want to do a zone

1:12:01

two test, okay? Can

1:12:04

you somehow use a percent

1:12:07

max rate, a heart rate, sorry, max heart

1:12:09

rate, like proxy to kind of know, like,

1:12:11

you know? Yeah, there are lots of different

1:12:13

ways to estimate this. And to be clear,

1:12:15

like, I'm one of the very few people

1:12:18

that is checking his lactate every, you know,

1:12:20

every day that he's on his bike, which is four

1:12:22

days a week for me. And by the way, I'm

1:12:24

also doing it while using all the other metrics that

1:12:27

I'll explain in a moment, mostly

1:12:29

just in an ever never ending quest

1:12:32

to just have as much data as

1:12:34

possible to understand when is

1:12:36

lactate the best predictor? When was RPE

1:12:38

the best predictor? When was heart rate

1:12:40

the best predictor? When was absolute wattage

1:12:42

the best predictor? Like, there's

1:12:44

a lot of stuff going on here. So first

1:12:47

thing I always say to people, namely my patients,

1:12:49

when they say, I don't want to

1:12:52

get that lactate meter. I don't want to be poking

1:12:54

myself in the finger. I'm like, great, don't, you don't

1:12:56

have to. There are like other ways

1:12:58

that you can pretty much approximate your zone two

1:13:00

output. And the only reason I brought up the

1:13:02

whole lactate testing is it is the gold standard,

1:13:04

and it is the most objective way to do

1:13:07

this. And therefore, if I'm trying to really understand

1:13:09

the impact of saying metformin or astatin, that's what

1:13:11

I want to do. But let's put that aside

1:13:13

for a moment and answer the relevant question, which

1:13:15

is, hey, how does someone exercise in this zone?

1:13:19

I think the most important, you

1:13:22

know, tool for virtually anybody

1:13:24

is rate of perceived exertion. I

1:13:26

think that will almost never let you down. In

1:13:30

fact, I would argue that

1:13:32

for a really, really out of shape individual,

1:13:34

rate of perceived exertion is even better than

1:13:36

lactate. And the reason for

1:13:38

that is you take somebody who's got, for example,

1:13:41

type two diabetes, their resting lactate may already be

1:13:43

at two. So

1:13:45

in those patients, we actually never use lactate.

1:13:47

Until you get somebody to a certain level

1:13:49

of fitness, we only use rate of perceived

1:13:51

exertion, and we will provide heart rate guidance.

1:13:54

So here's two ways to think about it. RPE,

1:13:58

rate of perceived exertion, give people

1:14:00

the test which is the talk test. So

1:14:03

when you are in zone 2 you

1:14:05

should be able to speak

1:14:08

to somebody but it should be uncomfortable

1:14:11

and not something you want to do. If

1:14:13

you can't speak you're

1:14:15

out of zone 2. If you

1:14:17

can't speak in a full sentence you're not in zone 2 anymore.

1:14:20

You're north of zone 2. If you can speak

1:14:22

the way you and I are speaking now you're

1:14:24

not working hard enough. You're too far below it.

1:14:27

So there is that sweet spot

1:14:29

where if you're on that peloton

1:14:31

and the phone rings and

1:14:34

you answer it the person knows you're

1:14:36

exercising and you're going to let them do most

1:14:38

of the talking. But if they

1:14:40

ask you a question and you have to answer it you'll answer it and

1:14:42

you can speak in a full sentence but you're not that comfortable. That's

1:14:45

the single most important thing people need to understand about it.

1:14:48

As far as what heart rate guidance comes with it,

1:14:53

filmafetone uses a test that I think is a

1:14:55

pretty good starting place which is 180 minus

1:14:57

your age. Now

1:14:59

the fitter you are the

1:15:01

less relevant that becomes. So I'm

1:15:04

50 so that would put me

1:15:06

at 130 but I can tell you my zone 2 is

1:15:08

above 130. So if

1:15:10

you're fitter you may add 5 to 10 to

1:15:13

that. I use another

1:15:17

app that checks my HRV

1:15:19

every single morning and it

1:15:21

predicts my zone 2 as

1:15:23

a result of my HRV.

1:15:26

And so every day what I'm doing

1:15:28

is I'm looking at the heart rate

1:15:30

predicted by the app which can vary by as much

1:15:32

as 10 beats per minute based on

1:15:34

how much I slept, the quality of my sleep, how

1:15:37

sore I am, a subjective measurement

1:15:39

of how much I want to train that

1:15:41

day and my HRV. So it's called

1:15:44

Morpheus. So

1:15:46

I have no affiliation with them or anything like that.

1:15:48

So basically this

1:15:51

morning I got up, my

1:15:53

HRV was I don't even remember,

1:15:55

78 milliseconds, slept

1:15:58

7 hours 15 minutes, good quality

1:16:00

sleep, not sore, felt

1:16:02

good. So I actually had a pretty

1:16:04

high target today. My target

1:16:07

today was 141 was the heart rate.

1:16:09

On a day, that's about as high as it will predict me

1:16:12

to be. On a day when everything

1:16:14

sucks, it might tell me as low as 129. Usually it's

1:16:18

about 136, 137, 138

1:16:20

is where it's predicting and that's generally aligning

1:16:22

with where my lactate is. That

1:16:25

will generally put me at a lactate of about 1.9. And then on

1:16:29

top of that, I'm paying attention to the wattage. So I

1:16:31

kind of know where to be. But again, for somebody just

1:16:34

starting out, RPE is all you need to know. 180 minus

1:16:37

your age is good and then the if

1:16:39

a person is fit enough that they truly

1:16:41

know their maximum heart rate, we

1:16:44

tell them to start at somewhere between 75 and 80% of that

1:16:46

number. So

1:16:50

if a person is specifically

1:16:53

trying to do this functional mitochondrial

1:16:56

test, how long should they

1:16:58

be in that zone too before they

1:17:00

can measure their lactate? We'd like to

1:17:02

see people there for 30 to 45

1:17:04

minutes before we do it. So a

1:17:06

true, true steady state. Awesome.

1:17:10

So I kind of want to, the

1:17:12

other going back, circling back to the statins. And

1:17:16

here's my question to you.

1:17:18

Okay. What

1:17:20

questions do you think I should be

1:17:23

asking and looking in the

1:17:25

literature to convince myself that

1:17:28

let's say a lipophilic statin that could,

1:17:32

you know, cross the blood-brain barrier, get

1:17:34

into the brain, inhibit, you

1:17:36

know, HEM, CoA in the brain, particularly

1:17:39

at higher doses. But generally

1:17:41

speaking, what

1:17:44

can, what question should I be asking myself

1:17:46

to convince myself that it's not going to

1:17:48

put me at a higher risk for both

1:17:51

of the neurodegenerative disease that I'm terrified

1:17:53

about, one Alzheimer's disease, I have a

1:17:55

genetic, it's family history, genetic risk factor,

1:17:58

and Parkinson's disease, family history. Both

1:18:00

of those diseases have been

1:18:02

associated with statin use. They've also been,

1:18:04

the literature as you know is, you

1:18:08

know, you can find what you want, right? So,

1:18:11

do you have any, you

1:18:13

know, if I can? Yeah, I did a recent

1:18:15

AMA on this. Although

1:18:17

it might not be out yet. I lose track of when I record

1:18:19

them and when they come out. So I apologize if it hasn't come

1:18:21

out yet. But I

1:18:24

did an entire AMA on this topic because it

1:18:26

is so important

1:18:28

and I think it's, as you said, it's

1:18:30

so confusing. So

1:18:33

I was actually surprised to learn this. I

1:18:36

was surprised to learn that there

1:18:38

has never, oh, I shouldn't have been

1:18:40

surprised, but, regardless, here's what it is.

1:18:42

There has never been a study done

1:18:44

that has looked at the use of

1:18:46

statins and the incidence of Alzheimer's

1:18:49

disease or dementia as a primary

1:18:51

outcome. Why is that important? It's

1:18:54

important because in clinical research, the primary outcome

1:18:56

is the only thing you can really take

1:18:58

to the bank because that's what the study

1:19:00

is powered to detect. There

1:19:02

are more

1:19:05

than a dozen, probably less than 25. So

1:19:10

a big number of studies, call it 15, 16, that

1:19:14

have used statins, have

1:19:16

had a primary outcome of

1:19:19

ASCVD, but a secondary outcome

1:19:21

of dementia or Alzheimer's disease.

1:19:24

And I looked at every single one of those. And

1:19:28

I can tell you that every

1:19:30

single one of those found neutral

1:19:32

to benefit of statin

1:19:35

use on the incidence of dementia and

1:19:38

the incidence of Alzheimer's disease.

1:19:40

So that includes vascular dementia.

1:19:43

I mean, that sort of makes

1:19:45

more sense. Parkinson's disease. Have you seen, have

1:19:47

you looked at the literature on that? So

1:19:50

Parkinson's is a little bit more confusing

1:19:52

because the literature is way more sparse.

1:19:56

But I do wanna go back and talk about Alzheimer's disease because

1:19:58

I think there's an important caveat to it. everything I just

1:20:00

said. What I basically – oh, the other

1:20:02

point I want to make Rhonda, this actually surprised me. There

1:20:05

was no difference between hydrophobic

1:20:10

and hydrophilic statins. With

1:20:13

respect to the – To these – Okay.

1:20:16

No difference whatsoever. So counterintuitive but

1:20:19

no difference whatsoever. So

1:20:23

even though, again, you might think, well, gosh, you know,

1:20:25

a statin that gets in the brain should have more

1:20:27

of an impact but it didn't seem to have –

1:20:29

Is there a difference in those two types of statins

1:20:32

with respect to the diabetes – increased

1:20:34

diabetes risk that you're talking about or is that

1:20:36

not known? That's a really good question. I didn't

1:20:38

look at that and that wasn't looked at in this –

1:20:41

Or maybe it's not, yeah. Yeah. Here's what

1:20:44

I can tell you. The highest incidence of

1:20:46

diabetes is probably with atorvastatin but

1:20:49

that might also be because atorvastatin is the most

1:20:51

widely used. Like I don't – Right. We

1:20:54

basically – first of all, there's

1:20:56

only four statins that I think are even worth

1:20:58

prescribing these days, maybe only three and I treat

1:21:00

them all equally in terms of risk. In other

1:21:03

words, I would assume any time you put somebody

1:21:05

on a statin, you should be looking for any

1:21:07

of the side effects and I don't particularly –

1:21:09

because again, at the – you might say

1:21:11

at the population level, it's different but at the

1:21:13

individual level, who cares? It's either one or zero.

1:21:16

You're going to get it or you're not. What

1:21:18

statins are those three? The ones that we would

1:21:20

prescribe would be resovastatin or crester, atorvastatin or lipitor,

1:21:23

atorvastatin, Livolo and sometimes we

1:21:25

use prevastatin or prevacol but

1:21:28

pretty rarely. So usually those

1:21:30

would be the big four. Now, here's

1:21:33

what I

1:21:35

would say and this

1:21:37

is something that we spend an awful lot

1:21:39

of time looking at in our practice and

1:21:41

actually just last week, Tom

1:21:44

Dayspring gave

1:21:46

us an internal presentation that was so incredible.

1:21:51

It was months in the making, looking

1:21:55

at the relationship

1:21:57

between statin use and desmash,

1:22:00

levels and dementia risk. So

1:22:03

you may recall a moment ago I mentioned

1:22:05

desmosterol. So desmosterol

1:22:08

is, well let's back up, remember

1:22:11

how I said there were two cholesterol synthesis pathways?

1:22:14

Well in the CNS really

1:22:16

only you have one pathway and it's

1:22:18

the pathway that goes through desmosterol to

1:22:21

cholesterol. So desmosterol

1:22:23

levels are actually a

1:22:25

decent proxy for brain

1:22:28

cholesterol synthesis. Lethosterol,

1:22:31

which is the penultimate molecule

1:22:33

in the other pathway, is

1:22:37

more of a proxy for peripheral

1:22:39

cholesterol synthesis. Are these measured?

1:22:41

You can measure these on a like...

1:22:43

They're very difficult to measure in most

1:22:45

labs. We use a lab that measures

1:22:47

them. So we measure desmosterol and

1:22:50

Lethosterol in every patient with every blood draw.

1:22:53

Unfortunately this is not standard of care.

1:22:55

Most labs can't measure this. Boston Heart

1:22:57

does this. That's why we use Boston

1:22:59

Heart. There

1:23:02

are enough data suggesting

1:23:05

that if desmosterol levels

1:23:07

are very low, the

1:23:09

risk of AD does indeed go up

1:23:12

and the risk of dementia

1:23:14

beyond AD goes up. So

1:23:17

this is you know kind

1:23:19

of what I would describe as personalized

1:23:22

medicine slash medicine 3.0 at its finest

1:23:24

which is you have

1:23:26

to treat every patient individually and

1:23:29

we're doubly careful in patients

1:23:31

with an ApoE4 gene and

1:23:34

or a family history. And in those

1:23:36

patients based on the literature and I'd

1:23:38

be happy to send you Tom's presentation. He would not

1:23:40

have a hard time with me sharing that even though

1:23:42

it was kind of an internal presentation. In fact I

1:23:45

could share with you the recording Tom made because we

1:23:47

recorded the internal meeting because it was so valuable. But

1:23:50

basically the cutoff we use is 0.8. So

1:23:53

if desmosterol falls below 0.8 milligrams

1:23:56

per deciliter, we

1:23:58

think the risk of depression is very low. dementia is

1:24:00

sufficiently high enough that we would abort the

1:24:02

use of the statin. Very

1:24:05

good information. And you think there is

1:24:07

a correlation with APOE status on that

1:24:09

number? No one has done

1:24:12

that study yet. In your clinical.

1:24:15

But in our clinical practice, we

1:24:17

just decided like why would we

1:24:19

take the risk? Okay. But yes,

1:24:21

no one has done the study

1:24:23

to show our desmossterol levels lower

1:24:25

in APOE4 individuals. That's actually a

1:24:27

very testable hypothesis and it makes

1:24:29

a lot of sense because

1:24:32

we know APOE is

1:24:34

heavily involved in cholesterol

1:24:37

activity in the brain. And so

1:24:39

it wouldn't be surprising to me

1:24:41

if you put people into three

1:24:44

buckets, zero alleles, one allele or

1:24:46

two allele, E4 alleles, and

1:24:48

then just looked at desmossterol levels. That would

1:24:51

be a very easy, mindless study to do.

1:24:53

Just a survey. Like just a

1:24:55

quick, is there a correlation? Yes or no? So

1:24:59

that's one thing I'd love to know the answer to. But

1:25:02

even absent that knowledge, our

1:25:05

view is there's simply

1:25:07

no reason to take the risk. You

1:25:10

know, earlier I said it makes no

1:25:12

sense to go on

1:25:15

some crazy, obscure diet that has a

1:25:17

whole bunch of unintended consequences just to

1:25:19

control your lipids. Well, I would make

1:25:21

the exact same statement here. It makes

1:25:23

no sense to get all, to

1:25:25

take unnecessary risks with statins in

1:25:28

a higher risk individual when we have these

1:25:30

other tools. We have, as we talked about

1:25:33

or we will talk about, isetamide, PCSK9 inhibitors,

1:25:35

bampidoic acid, these are unbelievable tools

1:25:37

that have no bearing on

1:25:39

brain cholesterol synthesis. But Peter, aren't

1:25:42

people that have an APOE4 allele

1:25:44

more likely to be prescribed

1:25:46

statins based on their LDL

1:25:49

particle number by their physician because

1:25:51

the physician doesn't look at their, none

1:25:53

of this. This isn't personalized. It's not medicine 3.0,

1:25:55

right? That's right. So, no, it's very frustrating.

1:25:59

And it's also frustrating that of those three

1:26:01

drugs that are an alternative to statins,

1:26:03

two of them are still very expensive.

1:26:06

Okay, so the three drugs, I know the

1:26:08

PCSK9 inhibitor. Yep. And

1:26:10

highly effective, insanely safe,

1:26:13

zero side effects, cheaper

1:26:17

than when they came out so they

1:26:19

were approved in 2015. We

1:26:22

have long term data with the people walking around

1:26:24

with a natural mutation, right? Just

1:26:26

amazing. Yeah, exactly. We have

1:26:28

a little experiment, we have all of the data from these

1:26:30

drugs and these drugs have been

1:26:32

tested in really good trials and they've gone head

1:26:35

to head with every drug and they always win

1:26:37

and there's no side effects. But

1:26:39

they're expensive, right? It's a $500 a month

1:26:41

drug in the United States. It's

1:26:43

cheaper outside of this country so everything's better out of

1:26:45

the US when it comes to drug pricing but in

1:26:47

the US you're talking about $500 a

1:26:50

month for that drug if it's not covered

1:26:52

by your insurance company. Right.

1:26:54

And if you can get a doctor to say,

1:26:56

I'm going to prescribe it to you. I mean like. I

1:26:59

mean at this point a doctor who doesn't,

1:27:01

who's not willing to prescribe a PCSK9 inhibitor

1:27:03

just is a fool. So

1:27:07

it's just a question of the cost

1:27:09

because unfortunately most insurance companies will not

1:27:12

cover it unless you meet certain criteria

1:27:14

such as having familial hypercholesterolemia or

1:27:17

having already had a cardiac event like

1:27:19

a heart attack and not

1:27:21

being able to tolerate a statin. What

1:27:23

about myopathy? Like if you have muscle. Yes. Significant

1:27:26

myopathy on multiple statins but

1:27:29

you'd also have to be at high enough risk

1:27:31

to justify it. So insurance companies are going

1:27:33

to go out of their way to not pay for this. Then

1:27:36

you have ezetimibe. Now ezetimibe is relatively

1:27:39

inexpensive. It's just not as

1:27:41

potent. So ezetimibe also

1:27:43

effectively serves to increase the LDL

1:27:45

receptors on the liver but

1:27:47

it does so by impairing cholesterol reabsorption. So it

1:27:49

blocks one of those two transporters I was talking

1:27:51

about in the gut. The first one. And

1:27:54

by blocking that the body is

1:27:56

absorbing way less of its own

1:27:58

cholesterol and the liver senses that and

1:28:00

the liver says, hey, I gotta get more cholesterol,

1:28:02

puts more LDL receptors on, pulls out circulation. It's

1:28:07

not as potent and as a monotherapy,

1:28:10

the only times we see

1:28:12

really head over heels responses

1:28:14

are in patients who have

1:28:16

defective ATP binding cassettes in

1:28:18

their gut and we measure that

1:28:21

by looking at phytosterol levels. So

1:28:23

we measure two things, one is

1:28:26

called phytosterol, one is called compesterol,

1:28:28

those are phytosterols, so these are

1:28:30

cholesterol we don't make, it's zosterol,

1:28:33

pardon me, it's phytosterol, not zosterol.

1:28:35

And so when we measure those

1:28:37

levels, we know that it speaks

1:28:39

to how much plant sterool is

1:28:41

being absorbed and not

1:28:44

being excreted. And so when

1:28:46

patients have really, really high

1:28:48

levels of phytosterols, you know

1:28:50

they have a defective ATP

1:28:52

binding cassette and those

1:28:54

patients respond really well to azetimide.

1:28:56

It's like a blockbuster in those

1:28:58

people. Is that

1:29:01

a common single nucleotide

1:29:03

polymorphism? It

1:29:06

depends how extreme it is. So

1:29:10

it's not uncommon to see people who are above

1:29:13

the 90th percentile, but

1:29:16

I've only seen probably three people

1:29:18

that have

1:29:21

a level that is so high you'd actually

1:29:23

be concerned with it, just in and of

1:29:25

itself, meaning like the actual level, because phytosterols

1:29:27

are actually more atherogenic than cholesterol. And

1:29:30

that's also like Boston Heart would

1:29:32

measure all these phytosterols, okay. They're

1:29:35

more atherogenic than cholesterol. Yeah, they're

1:29:38

more prone to oxidation, more inflammatory.

1:29:41

Are they being carried in

1:29:43

lipoproteins? So

1:29:46

are they oxidized, they're more oxidized? They're

1:29:48

more oxidizable, and this is by the

1:29:50

way is a reason that we don't

1:29:52

favor the practice of using phytosterols to

1:29:54

lower cholesterol. So there

1:29:56

are a lot of sort of over the counter treatments

1:29:59

where people use phytos... Sterols to lower their

1:30:01

cholesterol and they did does so

1:30:03

if you Ingest a ton

1:30:05

of phytosterols you will out compete

1:30:08

cholesterol at that Entrocyte

1:30:10

and your body will regulate and

1:30:12

you'll end up net

1:30:14

net reabsorbing less total cholesterol The

1:30:18

problem with that is if you have

1:30:20

a defective ATP binding cassette, which again

1:30:22

It's not that uncommon that you do

1:30:25

you will end up really absorbing a lot

1:30:27

of those phytosterols And again, they can so

1:30:29

this is an it's sort of an example

1:30:31

of that does master all point earlier where

1:30:33

you can lower cholesterol But if you're really

1:30:35

raising does master all too much it can

1:30:37

be more atherogenic than cholesterol in the first

1:30:39

place So does master all has shown up

1:30:41

twice today It showed up in

1:30:43

a good sense and in a bad sense So too

1:30:46

much of it if you're using a

1:30:48

drug that blocks the enzyme that comes after it

1:30:50

That was the thing that was producing too much

1:30:52

atherosclerosis in the 60s too little

1:30:54

of it Could be

1:30:56

a marker of to Too

1:30:59

little cholesterol synthesis in the brain and

1:31:01

that can be a whole problem on it And of itself the

1:31:03

final drugs we can just wrap this up because I'm sure the

1:31:05

listeners are tired of hearing about this stuff It

1:31:08

is a is a drug called bampadoeic acid.

1:31:10

There's a pro drug. This is very elegant

1:31:12

drug. It's taken as a pill But

1:31:16

it's ineffective until it's metabolized by the

1:31:18

liver and in the liver it then

1:31:20

inhibits cholesterol

1:31:23

synthesis what makes this drug

1:31:25

special is unlike statins

1:31:28

This drug only works in the liver so

1:31:30

statins work throughout the body They

1:31:33

do most of their work in the liver,

1:31:35

but technically every cell is impacted by a

1:31:37

statin Only hepatocytes

1:31:39

are impacted by bapindoic acid and

1:31:42

it lowers a pubi same way lowers

1:31:44

cholesterol synthesis liver says I need more

1:31:46

cholesterol puts more LDL receptors up pulls

1:31:48

more LDL in LDL and cholesterol go

1:31:51

down, but no side effects no type

1:31:53

2 diabetes Nothing nothing

1:31:55

nothing. It's just it's only acting

1:31:57

in the liver Well,

1:31:59

that's it That sounds uh... Same problem

1:32:01

is PCS-Ganine inhibitor, it's a $500 a month drug.

1:32:05

Okay. Yeah. So

1:32:08

again, we'd have every... Look, honestly at

1:32:10

this point, like if money were on

1:32:12

a... were no issue, you'd probably just

1:32:14

be on PCS-Ganine inhibitors, isetimibe and

1:32:16

bambanoic acid. I mean, eventually we'll get there, right? Yeah,

1:32:18

you just have to come down on price. For

1:32:21

people that want a like more clear picture

1:32:23

of the plaque accumulation in their arteries, in

1:32:27

their vascular system. The

1:32:30

best way to do it, I think I've

1:32:32

heard about... CT angiogram. CT angiogram, okay. And

1:32:35

is that something, you know, like you

1:32:37

think people should start at a certain age

1:32:39

or certainly if they have measured their, you

1:32:42

know, APOB and... Yeah, I

1:32:44

mean, you know, I think there's different ways to think about

1:32:46

this. You know, I

1:32:48

think there's a principle in medicine that

1:32:50

most doctors try to adhere to, which

1:32:52

is don't order a test unless there's

1:32:54

a chance the test will change your

1:32:56

management. Then

1:33:00

it's easy to deviate from that. I certainly know

1:33:02

I do at times, but as a general rule,

1:33:04

I try to ask myself the question, before I

1:33:06

order this test, how will the

1:33:08

outcome change what I do with this patient?

1:33:11

So through that lens, you could make a

1:33:13

case that the only time you

1:33:16

should be ordering a CT angiogram is if

1:33:18

you go through the following experiment, which is

1:33:20

if it comes back normal, how

1:33:23

will it change what I do? If it

1:33:25

comes back abnormal, how will it change what I do?

1:33:28

So if

1:33:30

you were sitting in my office and I said, well, look, Rhonda,

1:33:32

you're 35 years old, your

1:33:34

APOB is really high, your family history is

1:33:37

such that people get cardiovascular disease in your

1:33:39

family, meaning, you know, it's not like you've

1:33:41

got a bunch of relatives who are in

1:33:43

their 90s who have never had a cardiac

1:33:45

event. So you don't have some genetic protection

1:33:48

of cardiovascular disease. Do

1:33:50

I need a CT angiogram in you to convince

1:33:52

me to do anything? Because the truth of it

1:33:54

is, at 35, your CT angiogram is going to

1:33:57

be normal. I mean, it might not be.

1:33:59

Mine wasn't. at 35, but

1:34:01

it probably will be for most people. And

1:34:04

if it's normal, will I then say we don't need to

1:34:06

do anything about this? No, because

1:34:08

that's sort of like saying you're a smoker

1:34:11

who has a normal CT scan. You don't yet have lung

1:34:13

cancer, therefore we should let you keep smoking. No, we should

1:34:15

stop you from smoking. So in other words, I

1:34:17

just wouldn't have a huge appetite for doing that test in

1:34:19

you. There

1:34:21

are other patients at the other end of the spectrum

1:34:24

where, you know, they come to me, they're 75 years

1:34:26

old, their Apo B is through the roof. But

1:34:29

I noticed like all their relatives live to be 100

1:34:32

and they never had heart disease. And

1:34:35

I look at them and I think, do I really want to

1:34:37

put this person on lipid lowering medicine at the age of 75?

1:34:40

Why don't we do a CTA? If

1:34:42

the CTA is normal, which by some

1:34:45

miracle it could be, I don't

1:34:47

think we need to do something. There's clearly something

1:34:49

this person has going on that is beyond our

1:34:51

understanding of the science so far. So

1:34:54

in that sense, I wouldn't do anything about it. The

1:34:57

way I think about it is there's a two

1:34:59

by two, which is age versus

1:35:03

finding, positive or negative. I

1:35:06

think CT angiograms are mostly helpful when they

1:35:08

have a positive finding in a young person

1:35:10

or a negative finding in an old person.

1:35:13

That's where it can really cause you

1:35:15

to act differently. Outside

1:35:17

of those findings, i.e. positive findings in old

1:35:20

people are to be expected, negative findings in

1:35:22

young people are to be expected. I think

1:35:24

you should just track the biomarkers of interest

1:35:26

and go off that risk. Okay. I

1:35:29

mean, is a 45-year-old considered? I would still put

1:35:31

that in a young category. Okay. Especially

1:35:33

for a woman. You think that CT angiogram would still kind

1:35:36

of look maybe

1:35:38

good. It should. And

1:35:40

again, I would only think about it through the lens of if

1:35:42

the patient is hesitant. So

1:35:45

we had a new patient that started a couple

1:35:47

of weeks ago. He'd never had one of these

1:35:49

tests before. But

1:35:52

he had a lot of risk factors, right? Elevated APO

1:35:55

B, elevated LPa, I

1:35:57

mean, two big risk factors. And

1:36:00

but but insanely healthy individual like very

1:36:02

very healthy individual. So so on the

1:36:05

surface like nobody thought anything of this

1:36:07

this person. We

1:36:11

decided we were going to treat him regardless and he was

1:36:13

completely on board with that. But the question was how aggressively

1:36:15

would we treat and we

1:36:17

said let's let the CTA decide that if

1:36:19

the CTA comes back clean as a whistle. We're

1:36:23

going to treat you to like an a po B of

1:36:25

60 which

1:36:27

is still aggressive by most people standards by our standards.

1:36:29

It's sort of middle of the road aggression if

1:36:32

the CTA comes back and there's a problem

1:36:34

meaning you have calcification and soft plaque. We're

1:36:37

going to treat you to 30 or 40. So

1:36:39

there the CTA helped us make a difference

1:36:41

at a real treatment difference and this is

1:36:43

a person who's you know middle

1:36:46

age. So not too old not too young. That makes a lot of

1:36:48

sense before we you

1:36:50

know kind of shift gears and let

1:36:52

us know the things I want to ask you about. Have

1:36:56

you looked like I know I know you've mentioned it's

1:36:58

been a many years since I've already talked about berberine.

1:37:00

But I you know every once in

1:37:02

a while I'll get a question and I decide I

1:37:05

want to dive into literature and see if there's anything

1:37:07

new right. So that happened recently my team

1:37:10

and I did a deep dive into berberine

1:37:12

and its effects on you know clearing away

1:37:14

existing plaque on lowering you know LDL particle

1:37:16

number possibly total

1:37:19

LDL cholesterol level. But

1:37:21

I was surprised. Yeah what did you find? So

1:37:23

there was a systematic review and it was 2022

1:37:25

I believe. And

1:37:30

these are all like we need this is sparse

1:37:33

data right systematic review of what the existing literature

1:37:35

was which isn't a huge body of evidence. But

1:37:38

so there was a bunch of studies that looked at

1:37:40

berberine and you know varying

1:37:42

doses and then looking at it in

1:37:44

conjunction with statins or comparing it to statins

1:37:46

or comparing it to a placebo. And

1:37:49

it pretty much to me was convincing

1:37:51

that it was beneficial in every in

1:37:53

every single scenario. So berberine alone berberine

1:37:55

alone was lowering the LDL

1:37:58

cholesterol and I can't remember. if

1:38:00

it was particle number, but it was L-D-O.

1:38:02

And it's interesting, berberine is also a mitochondrial

1:38:04

toxin. Really? Yeah. Berberine

1:38:07

is an analog of metformin. So

1:38:10

it's a complex one inhibitor. Is it? Really? Wow,

1:38:13

I didn't know that. It was

1:38:15

like, it was to me looking really beneficial, where

1:38:17

it was like, it was- I'm not saying that wouldn't

1:38:19

be. I'm just sort of pointing out. Like, it's interesting.

1:38:21

Is there literature showing that? Or is it like an

1:38:23

in vitro kind of thing, where it's like, mechanistically? God,

1:38:25

I don't remember. It's been so long since I've looked

1:38:27

at berberine. But berberine

1:38:30

is kind of a poor man's metformin. OK. Well,

1:38:33

it was- And that's the way I thought about it. I think I'd

1:38:35

heard you talk about it years ago, maybe on Tim's

1:38:37

podcast. I don't remember. It was a long time ago.

1:38:39

Yeah. And that's kind of where I even first heard

1:38:41

of berberine, with you. And I remember

1:38:43

because I was going for Iran. It was when I lived in Oakland.

1:38:46

And then I was like, berberine, what's that? And

1:38:48

I remember you talking about it in the context

1:38:50

of, I think, metabolic health. Yeah. And

1:38:52

in kinase or something. Should lower glucose. Should inhibit

1:38:54

it automatically. Yeah. But this data on the lip,

1:38:57

it was very interesting. And I linked it in

1:38:59

that document. And what was the magnitude of effect?

1:39:01

I don't like you. It's

1:39:03

in that document. It's linked. OK. The studies, the

1:39:06

meta-analysis. You can look at it because I don't

1:39:08

remember everything. But what I do know

1:39:10

is it also lowered the side effects of statin

1:39:12

myopathy. Was one in particular. It

1:39:15

lowered the dose, effective dose of

1:39:17

statins that was needed to lower the

1:39:19

LDL. Interesting. Very

1:39:21

interesting, right? Yeah, I'll check that

1:39:24

out. I actually ordered some berberine.

1:39:27

Maybe I should test this and see

1:39:29

how. And there are companies like Thorne

1:39:31

and it. I ordered Thorne, yeah, which I have

1:39:33

no affiliation with. I just trust their brain. So

1:39:36

anyways, I wanted to bring that up because I

1:39:39

know that, again, I'd heard a berberine from you

1:39:41

years ago. But speaking

1:39:43

of metabolic health, and you kind of talked

1:39:45

about this earlier with

1:39:48

continuous glucose monitoring and measuring

1:39:50

your fasting glucose and

1:39:53

also your response to foods. And

1:39:56

so what glucose

1:39:59

disposal is something. thing that you've talked about.

1:40:02

People always hear about fasting glucose,

1:40:04

HbA1c, like what should those numbers

1:40:06

be? But also, what is glucose

1:40:09

disposal and why should people be

1:40:11

paying attention to that and can

1:40:13

they use CGM to sort of

1:40:15

measure that? Yeah, yeah. Glucose

1:40:18

disposal is, take

1:40:21

a step back, glucose regulation is just, it's

1:40:23

such a miracle of our physiology. I mean,

1:40:25

there's, every time I think about biology,

1:40:27

I'm really grateful

1:40:29

that I've came to

1:40:32

this field in one way or another,

1:40:34

because it leaves you endlessly at awe

1:40:36

of what's happening. So the interplay

1:40:39

between our endocrine system, our

1:40:45

liver, our muscles, in

1:40:47

terms of how glucose is regulated, is so

1:40:50

complicated and exists

1:40:52

on such a fine, fine line that

1:40:56

it is humbling. So let's just put

1:40:58

some of these numbers in perspective. So

1:41:01

most people who have had a blood test would recognize that

1:41:04

a fasting blood glucose of 100 milligrams

1:41:06

per deciliter is sort of right on the cusp of

1:41:08

being just starting to get to be too high. So

1:41:11

what does that mean, right? What is 100

1:41:14

milligrams per deciliter? Well, it means that in

1:41:16

someone my size, in all

1:41:18

of my plasma floating around, all of my body,

1:41:20

all of my blood, I have five grams of

1:41:22

glucose. So do I

1:41:25

have more than five grams of glucose in my

1:41:27

body? Of course I do, I have way more

1:41:29

than that. But the majority of the glucose in

1:41:31

my body is either in my liver or in

1:41:33

my muscles. There's only five paltry grams, 20

1:41:36

calories worth of glucose in

1:41:38

my entire circulation at this moment in time.

1:41:41

Now, if you assume for a moment that

1:41:44

I'm just sitting here at rest and

1:41:46

nothing in my body is demanding

1:41:48

glucose, meaning my muscles

1:41:50

aren't requiring it, the only organ that should

1:41:52

be really demanding it at the

1:41:55

moment is my brain. Now,

1:41:58

of course my red blood cells demand it have

1:42:00

mitochondria so they're gonna have to use glucose

1:42:03

and of course the kidney uses it and all sorts of

1:42:05

other things but basically the majority

1:42:07

of the glucose in my bloodstream at

1:42:09

this moment in time is being is

1:42:12

there for the purpose of my brain and

1:42:15

you know you

1:42:17

can do the math on this anybody can do the

1:42:19

math on this within a number of minutes I

1:42:22

will go through that 5 grams so

1:42:25

where does the next drop of glucose

1:42:27

come from? Comes from my

1:42:29

liver. So my liver

1:42:31

is constantly titrating just a

1:42:33

little bit of glucose into

1:42:36

my circulation to make sure that number

1:42:38

never goes from say a hundred where

1:42:41

it is now down to 50 because

1:42:43

that would be way too low but

1:42:46

it's never putting so much in that that number

1:42:48

would be 150 or 200 at that

1:42:51

point I would be full-fledged

1:42:53

type 2 diabetes so

1:42:56

the difference between you

1:43:00

and me if I have type 2 diabetes is

1:43:03

literally a teaspoon of glucose in our

1:43:05

circulation at any point in time think

1:43:08

about how tiny a difference

1:43:10

that is and

1:43:12

that speaks to this

1:43:14

enormous capacitor and buffer

1:43:17

subsystem of our liver and our muscles

1:43:19

so if

1:43:22

the liver is the thing that is

1:43:24

responsible for the the doling out of

1:43:26

glucose into circulation the muscle

1:43:28

is primarily responsible for where we put

1:43:30

glucose when it gets flooded into our

1:43:33

system and that happens every time you

1:43:35

eat so you eat and

1:43:38

again let's just do some easy math on

1:43:40

this like you eat a bowl of pasta

1:43:42

like not a peter bowl

1:43:44

which is like the size of my head

1:43:46

but just a normal sized bowl you're easily

1:43:48

getting 60 grams of glucose so

1:43:52

you eat 60 70 80 grams of glucose well remember

1:43:56

what I just said a moment ago like

1:43:58

if your blood level goes from five to

1:44:00

10 grams, you're hosed. Like

1:44:02

that's a really big problem.

1:44:05

Now, acutely it's not the end of the world, right? But

1:44:08

a healthy person would probably never go from

1:44:11

five to eight, more than

1:44:13

eight grams. So how do

1:44:15

you get that other 60 grams

1:44:18

of glucose away? You have to

1:44:20

put that into the muscles. And so

1:44:22

the muscle is the sink for glucose